Lipid metabolism reprogramming in head and neck cancer

Abstract

Lipid metabolism reprogramming is one of the most prominent metabolic anomalies in cancer, wherein cancer cells undergo dysregulation of lipid metabolism to acquire adequate energy, cell membrane building blocks, as well as signaling molecules essential for cell proliferation, survival, invasion, and metastasis. These adaptations enable cancer cells to effectively respond to challenges posed by the tumor microenvironment, leading to cancer therapy resistance and poor cancer prognosis. Head and neck cancer, ranking as the seventh most prevalent cancer, exhibits numerous abnormalities in lipid metabolism. Nevertheless, the precise role of lipid metabolic rewiring in head and neck cancer remains unclear. In line with the LIPID MAPS Lipid Classification System and cancer risk factors, the present review delves into the dysregulated molecules and pathways participating in the process of lipid uptake, biosynthesis, transportation, and catabolism. We also present an overview of the latest advancements in understanding alterations in lipid metabolism and how they intersect with the carcinogenesis, development, treatment, and prognosis of head and neck cancer. By shedding light on the significance of metabolic therapy, we aspire to improve the overall prognosis and treatment outcomes of head and neck cancer patients.

1 Introduction

Reprogramming of lipid metabolism is a critical hallmark of cancer. In recent years, dysregulated lipid metabolism has emerged as a focal point in cancer research (1). Physiologically, lipids play essential roles as energy sources, vital building blocks for cell membranes, as well as first and second messengers in molecular recognition and signaling processes (2, 3). Pathologically, any disturbance in lipid metabolism would significantly impact serious cellular behaviors, such as cell proliferation, differentiation, apoptosis, and motility, ultimately contributing to carcinogenesis and cancer development (3). In addition, rewiring of lipid metabolism impacts the treatment effects and the outcomes of cancer patients (4). Thus, lipid metabolism-related molecules and pathways have been proposed to be novel targets of anti-cancer treatment.

Head and neck cancer (HNC) comprises a group of tumors that predominantly arise from subsites within the oral cavity, oropharynx, hypopharynx, and larynx (5). It ranks as the seventh most common cancer worldwide, with more than 890,000 new cases and 450,000 deaths each year (6). Head and neck squamous cell carcinoma (HNSCC) accounts for approximately 90% of all HNC cases (7). Infection of human papillomavirus (HPV), tobacco use or smoking, and alcohol consumption are the three well-known risk factors for head and neck cancer (6, 8). Despite notable advancements in diagnosis and treatment, the 5-year overall survival rate for head and neck cancer patients with an advanced stage is 50% to 60%, indicating an urgent demand for further investigation into the underlying mechanisms of head and neck cancer carcinogenesis (9).

Lipid metabolism reprogramming is also linked to the carcinogenesis and development of head and neck cancer. Cancer cells actively promote the lipolysis process. And in turn, the various endpoints of lipid metabolism, including the oxidation of fatty acids, the generation of signaling lipids, epigenetic modifications of proteins, synthesis of cell membrane lipid, and other crucial processes, profoundly affect the malignant characteristics of cancer cells. Accumulated studies have described the dysregulated levels or activities of enzymes and molecules associated with lipid metabolism in head and neck cancer. Alterations of lipid profile in head and neck cancer are evident; for instance, there’s an elevation of fatty acid C16:0 and a reduction in total ceramide (10). In addition, overexpression of crucial components in lipid metabolism, such as cluster of differentiation 36 (CD36), fatty acid-binding protein (FABP), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FASN), have been well-documented in head and neck cancer (11–14). Hence, the molecules involved in the lipid metabolism alteration hold potential as novel biomarkers for the treatment and prognosis of head and neck cancer. Nonetheless, the precise role and underlying mechanisms of lipid metabolism in the context of head and neck cancer remain inadequately understood.

According to the LIPID MAPS Lipid Classification System, lipids are divided into eight categories, known as fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides (15). In the present review, based on the lipid classification system and cancer risk factors, we focused on the dysregulation of lipid metabolism and its implications on the carcinogenesis, treatment, and prognosis of head and neck cancer. Novel dysregulated molecules and signaling pathways participating in the process of lipid uptake, de novo synthesis, transportation, catabolism, as well as their roles in the composition of lipid profiles, would be involved and discussed, aiming to provide an updated and comprehensive understanding of this field and potential strategies for personalized treatment of head and neck cancer (Figure 1, Table 1).

Figure 1

2 Lipid metabolism reprogram in head and neck cancer

2.1 Alteration of fatty acid metabolism in head and neck cancer

Fatty acids are composed of saturated or unsaturated hydrocarbon chains terminating with distinct carboxylic acid groups. Mammals acquire fatty acids from the surrounding environment or by synthesizing de novo (31). The metabolism of fatty acids encompasses two key biological processes: fatty acid synthesis and fatty acid oxidation (FAO) (32).

2.1.1 De novo biosynthesis and catabolism of fatty acids

Fatty acid biosynthesis occurs in the cytosol. The first step involves the conversion of acetyl-CoA into malonyl-CoA through the activation of ACC. This, along with the participation of enzymes such as FASN, leads to the generation of palmitate (FA16:0). Subsequently, elongation processes produce fatty acids of different lengths. These fatty acids can then be esterified with glycerol or sterol skeletons, forming triacylglycerol (TG) or sterol esters, respectively. Finally, they are stored as lipid droplets (LDs) (33). On the other hand, fatty acid catabolism involves the activation of FAs in the cytoplasm to form acyl-CoA. The formed acyl-CoA is then transported to the mitochondrial matrix by carnitine palmitoyltransferase 1 (CPT1) for oxidation (34).

2.1.2 Altered fatty acid profile in head and neck cancer

Dysregulated lipid metabolism in head and neck cancer patients results in a distinctive fatty acid profile. In the context of oral squamous cell carcinoma (OSCC) tissues, it was noted that when compared with healthy controls, the level of fatty acids was frequently elevated, with the most significant increase observed in palmitic acid (C16:0), followed by oleic acid (C18:1) (16). In another study including 30 OSCC patients, Domagala et al. noted a remarkable increase of C16:0 in tumor, adjacent tissue, and blood serum samples. Independent of tumor grade, the levels of oleic acid (C18:1n9), erucic acid (C22:1n13), docosatetraenoic acid (C22:4n6), docosapentaenoic acid (C22:5n3), and nervonic acid (C24:1) were found to be more abundant in tumor-adjacent tissues than in serum, suggesting the potential roles of these fatty acids in promoting tumor progression in OSCC (10). In an explorative study, Laurell et al. compared the circulating lipidomic profile of HNC patients one year before and after treatment. A specific pattern emerged for FA 14:0, 18:3n3, and 20:3n6, showing an early reduction in FA 14:0 and late reductions in FA 18:3n-3 and 20:3n-6. Additionally, FA 14:0 was associated with changes in body weight (17). Taken together, the level of C16:0 is supposed to be increased in head and neck cancer. Nevertheless, a definitive fatty acid profile specific to head and neck cancer remains elusive. To address this, further investigation with a larger sample size and a more rigorous study design is imperative.

2.1.3 Increased fatty acids uptake in head and neck cancer

2.1.3.1 Cluster of differentiation 36

CD36, known as a fatty acid translocase, is responsible for binding and trafficking FAs from the exogenous environment into host cells. Its upregulation has been consistently observed in various human cancers, such as colorectal cancer (35), gastric cancer (36, 37), hepatocellular carcinogenesis (38), and melanoma (39). CD36 plays a vital role in modulating cancer development, metastasis, therapy resistance, and prognosis (40–44). Notably, CD36 is highly expressed in HNC (11, 45–47). Increased expression of CD36 was significantly associated with higher tumor status, tumor grading, and lymph node metastasis rate, exhibiting an over 40-fold increase in oral cancers (45, 46). An intriguing study by Pascual et al. reported that dietary palmitic acid could activate CD36 and accelerate cancer growth in OSCC, suggesting that dietary intake of fatty acids might play a role in CD36 modulation (48). In mice model, inhibition of CD36 has been shown to attenuate the metastasis of several cancers (41, 49, 50), including HNSCC (45). In particular, depletion of CD36 led to a significant inhibition of the lung metastasis ability of OSCC cells (45). Taken together, these findings suggest that CD36 could be a promising therapeutic target for clinical intervention of head and neck cancer.

2.1.3.2 Fatty acid-binding proteins

FABPs are important lipid chaperones, facilitating the transportation of long-chain fatty acids (LCFAs) to specific cell compartments. There are a series of members in the FABP family. The abnormal expression of FABPs in malignant tumors is associated with carcinogenesis, progression, and prognosis (51–55). In the case of HNC, there is notable upregulation of epidermal FABP (E-FABP, also known as FABP5), which might contribute to cancer proliferation and invasiveness (56–58). E-FABP, regulated by the epithelial cell adhesion molecule (EpCAM), is suggested to be a potential target of the oncogene c-Myc, leading to enhanced cell proliferation (57). Interestingly, according to Uma et al., FABP5 exhibited a lower expression in metastatic lymph nodes when compared with the corresponding primary squamous cell carcinoma of the oral tongue tumors (12). Yet, more samples are needed to confirm the conclusion. Furthermore, a study by Ohyama et al. reported abnormal expression of FABP4 and FABP5 in tongue carcinoma. Besides, the cytoplasmic staining for FABP5 was increased in tongue carcinoma patients with advanced T-stage and clinical stage, implicating that FABP5 might be a pathological marker (59). However, the precise mechanisms of FABPs in head and neck cancer need further research and investigation.

2.1.4 Dysregulated fatty acids synthesis in head and neck cancer

2.1.4.1 Acetyl-CoA carboxylases

ACCs serve as rate-limiting enzymes in fatty acid synthesis, playing a crucial role in catalyzing the carboxylation of acetyl-CoA to malonyl-CoA (60). The two isoforms of ACC, namely ACC1 (ACCα) and ACC2 (ACCβ), are enriched in lipogenic and oxidative status, respectively (61). ACCs are highly expressed in several cancer types, including prostate cancer, breast cancer, and HNC (62–64). Notably, elevated expression of ACC2 in laryngeal carcinoma correlates with advanced clinical cancer stage, lower cancer differentiation degree, as well as poor survival rates (64). It is known that ACC is regulated by AMP-activated protein kinase (AMPK) via phosphorylation (65). The same modulation also applies within the context of head and neck cancer (66). HNSCC cells with ACC mutations and lacking the AMPK phosphorylation sites, showed resistance to cetuximab treatment (67). With the combination treatment of ACC inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) and cetuximab, the growth of cetuximab-resistant HNSCC xenografts was effectively suppressed, suggesting that ACC can rewrite cancer metabolism from glycolysis-dependent to lipogenesis-dependent way (67). However, Chen et al. reported that an enhanced level of pACC was independently associated with poor overall survival of HNSCC patients, particularly in patients with lymph node-metastasis and advanced stage (13). The potential causes of contradiction may stem from various factors, including different ACC subtypes, diverse confounding factors (e.g., TNM stage, primary tumor site), and variation in experimental systems (e.g., in vivo, in vitro, or patient-based studies), among others. Additionally, phosphorylation of ACC is not only governed by AMPK; other kinases such as protein kinase C (PKC) and casein kinase 2 (CK2) also serve as regulators (60) Therefore, further evaluation is warranted to explore the modulation of ACC and its role in head and neck cancer.

2.1.4.2 Fatty acid synthase

FASN is a critical enzyme responsible for generating long-chain fatty acids from acetyl-CoA and malonyl-CoA (68). The level of FASN is naturally low or even undetectable in most human tissues except lactating breasts and cyclical endometrium, as the daily requirements of fatty acids are adequately met by food consumption (68, 69). In contrast, high levels of FASN are observed in various malignancies, which have been linked to increased risks of cancer metastasis, recurrence, and poor survival (70–74). In accordance with this, the expression of FASN is obviously elevated in HNSCC (14, 75–77). Salivary gland carcinoma, including well-differentiated carcinoma (secretory carcinoma, acinic cell carcinoma, etc.), high-grade adenoid cystic carcinoma, and mucoepidermoid carcinoma, also show an increased level of FASN, suggesting its potential role as an indicator of cancer aggressiveness and differentiation (78). Upregulation of FASN is required for the proliferation of oral squamous carcinoma (79). Pathological analysis has indicated that FASN expression was correlated with lymphatic infiltration, perineural infiltration, and regional lymph node metastasis status in OSCC (76). Moreover, high expression of FASN was related to poor prognosis and might be an indicator of pulmonary metastasis in patients with HNSCC (76, 77, 80).

FASN is positively regulated by the cell surface receptor ErbB2 in HNSCC (75, 80, 81), though the precise correlation and underlying mechanisms need further investigation. As a FASN inhibitor, orlistat has demonstrated promising effects in inhibiting the proliferation and metastasis of orthotopic tongue oral squamous cell carcinoma (82). Further, in vivo studies have shown that orlistat reduces the cervical lymph node metastasis rate by 43% (82). Additionally, orlistat or FASN siRNA treatment increased cell cytotoxicity and cell sensitivity to radiotherapy in the radioresistant HNSCC cell line rSCC-61 (83). Orlistat also increased the chemosensitivity of OSCC cells to cisplatin and paclitaxel by downregulating cyclin B1 (84). Moreover, other FASN inhibitors, such as C75 and Tvb-3166, have been shown potential as antineoplastic agents (84, 85). Further research is needed to explore the therapeutic implications of targeting FASN in HNC treatment.

2.1.4.3 Stearoyl-CoA desaturase

SCD is a lipid-modifying enzyme catalyzing the mono-saturation of oleate (18:1) and palmitoleate (16:1) (86). There are two isoforms of SCD (SCD1 and SCD5) required for human lipid metabolism (87). In a series of human malignancies such as lung, breast, colorectal, and bladder cancers, SCD is found to be overexpressed, and its upregulation is associated with tumor aggressiveness, making it a novel prognostic marker (88–90). In OSCC, elevated expression of SCD was negatively correlated with survival (91). Interestingly, overexpression of SCD was detected not only in HNSCC cell lines but also in tobacco-treated normal oral keratinocytes. Inhibition of SCD hampers cell proliferation, invasion, and colony formation, suggesting the potential roles of SCD and tobacco in the carcinogenesis of HNSCC. Thus, SCD has been proposed as a therapeutic target for HNSCC patients, particularly those with a history of tobacco use (92).

2.1.4.4 ATP citrate lyase

ACLY is a cytosolic enzyme which is responsible for acetyl-CoA synthesis during de novo lipogenesis (93). It is frequently upregulated in various malignancies, such as colorectal cancer (94), glioblastoma (95), endometrial cancer (96), and non-small cell lung cancer (97). In HNSCC, ACLY is also upregulated (91, 98) and its heightened expression is associated with an unfavorable prognosis (98). In addition, elevated ACLY expression is associated with the failure of radiotherapy. Notably, treatment of HNSCC cells with the ACLY inhibitor BMS303141 has been demonstrated to facilitate radiosensitivity via disturbing the DNA damage repair process (98), implying the potential role of ACLY inhibitor as a sensitizer for head and neck cancer treatment. Additionally, acetyl-CoA, generated by ACLY, is essential for acetylation reactions, particularly histone acetylation. Thus, ACLY is a critical node which links cellular metabolism to epigenetic modification. In nasopharyngeal carcinoma, ACLY is found to be protected from ubiquitin degradation through its interaction with the long noncoding RNA TINCR, thereby promoting cancer cell proliferation, metastasis, and chemotherapy resistance (99). Nonetheless, there’re limited reports on the role of ACLY in head and neck cancer, warranting further in-depth investigation.

2.1.4.5 Sterol regulatory element binding proteins

SREBPs is a family of transcription factors located in the endoplasmic reticulum. In mammalian cells, three SREBPs (SREBP-1a, -1c, and -2) are expressed, which are encoded by SREBP1 and SREBP2, respectively. Among them, SREBP1 is a major transcriptional regulator of fatty acid synthesis, while SREBP2 is mainly responsible for cholesterol metabolism, which will be discussed later. SREBP1 is highly activated in cancers, and its overexpression is correlated with increased cancer aggressiveness (100–105). It has been reported that overexpression of SREBP1 is necessary for HNSCC cell proliferation and migration (106). Furthermore, SREBP1 is noted to be an important linker between tumor protein p63 (TP63) and fatty acid metabolism, suggesting its potential role as an independent prognostic and therapeutic marker in HNSCC (106). Consistently, Su et al. reported that SREBP1 functions as an oncogene via upregulating steroidogenic acute regulatory protein-related lipid transfer 4 (STARD4) and promoting immune cell infiltration in HNSCC (107). Furthermore, SREBP1-mediated cell survival is disturbed by antioxidant resveratrol by inducing autophagy and subsequently inhibiting lipid metabolism in oral cancer (108). Hence, SREBP1 is postulated to function as an oncogene, suggesting its potential as a viable treatment target of head and neck cancer.

2.1.5 Increased fatty acids oxidation

Physiologically, fatty acids are catabolized via the mitochondrial fatty acid β-oxidation (FAO) pathway to meet the human daily energy requirements (109). In carcinogenesis and tumor progression, FAO plays a vital role in modulating various malignant behaviors, for example, tumor growth, survival, stemness, drug resistance, and metastasis (110).

2.1.5.1 Carnitine palmitoyl transferase 1

The first and rate-limiting step of FAO is catalyzed by CPT1, comprising three isoforms, CPT1A, CPT1B, and CPT1C (111). CPT1 has been extensively studied in a variety of cancers, and overexpression of CPT1A accelerates tumor development by stimulating FAO in prostatic cancer (112), breast cancer (113), gastric cancer (114), and hepatocellular cancer (115). In addition to its role in FAO, CPT1 plays a pivotal role in a series of signaling pathways to modulate the gene expression, apoptosis, and neovascularization (116). Intriguingly, CPT1 is another molecular linking lipid metabolism and epigenetic modification. CPT1 coimmunoprecipitates with histone deacetylase 1 (HDAC1) in the nuclear extracts from MCF-7 cells, promoting tumor cell proliferation (117). Treatment with HDAC inhibitors decreased the nuclear expression of CPT1 (117), indicating the potential role of CPT1 as a therapeutic target for epigenetic and metabolic interventions in cancer. However, research on CPT1 in head and neck cancer remain limited. According to Cao et al., CPT1A was consistently activated in radioresistant nasopharyngeal carcinoma (NPC) cells, and was positively correlated with the poor overall survival of NPC patients undergoing radiotherapy. In oropharyngeal squamous cell carcinoma, Barros-Filho et al. confirmed that elevated CPT1A expression was associated with poor survival (118). However, in HNSCC, Lin et al. observed no statistically significant correlations between CPT1 expression and patient age, as well as no statistically significant differences in CPT expression between early and late tumor stages (T1/T2 stage vs. T3/T4 stage) (119). Thus, it is imperative to conduct further investigation into the role and associated mechanisms of CPT1 in head and neck cancer, and election bias or other confounding factors should be taken in to consideration.

2.2 Alteration of glycerolipid metabolism in head and neck cancer

2.2.1 De novo biosynthesis and catabolism of glycerolipid

The synthesis of glycerolipid utilizes fatty acyl-coenzyme A (FA-CoA) and glycerol-3-phosphate (Gly3P) as substrates. FA-CoA condenses with Gly3P via glycerophosphate acyltransferase, leading to the formation of lysophosphatidic acid (LPA). LPA is subsequently converted to phosphatidic acid by 1-acyl-sn-Gly3P acyltransferase (AGPAT), followed by the production of diacylglycerol (DAG) through the functions of phosphatidic acid phosphatase (PAP) or phospholipids (PLs). DAG, in turn, generates TG by activating DAG acyltransferase (DGAT) (120). During the catabolism of neutral TG, adipose triglyceride lipase (ATGL) first converts TG into diacylglycerols (DGs), and then hormone-sensitive lipase (HSL) hydrolyzes DGs to form monoacylglycerols (MGs). Finally, MG lipase (MGL) hydrolyzes MGs and generates fatty acids and glycerol (121).

2.2.2 Altered glycerolipid profile in head and neck cancer

It has been reported that the plasma level of triglyceride is significantly lower in HNC patients (18, 19). Constantly, a notable decrease of triglyceride was revealed in HNSCC and lymph node metastasis tissues by high-resolution magic-angle spinning (HR-MAS) proton NMR spectroscopy (20). Furthermore, the serum level of triglyceride in precancerous oral lesions as well as oral cancer was found to be reduced when compared with healthy controls. Similarly, the plasma level of triglycerides was also decreased in oral cancer patients when compared to pre-cancerous subjects (21).

2.2.3 Dysregulated glycerolipid biosynthesis and catabolism in head and neck cancer

2.2.3.1 Adipose triglyceride lipase

ATGL, also known as phospholipase A2 (PLA₂), or patatin-like phospholipase domain containing 2 (PNPLA2), functions as a key enzyme hydrolyzing TGs to DAGs. Dysregulated expression of ATGL has been noted in a series of human cancers. The expression of ATGL in lung cancer is enhanced, indicating an unfavorable survival (122). Increased ATGL has been shown to promote the tumorigenesis of colon cancer in an obesity-augmented manner (123). In HNSCC, including oral cancer and tongue cancer, Ramamoorthy et al. reported a significantly increased activity of ATGL (124). Conversely, our research showed that ATGL was downregulated, leading to lipid droplets accumulation in NPC. Furthermore, decreased ATGL was associated with poor prognosis of NPC (125, 126). The variation of ATGL expression might be due to different anatomical regions of the HNSCC. Moreover, the mechanisms underlying the role of ATGL in head and neck cancer need further evaluation.

2.3 Alteration of glycerophospholipids metabolism in head and neck cancer

2.3.1 De novo biosynthesis and catabolism of glycerophospholipids

The substrate of glycerophospholipid biosynthesis is fatty acyl-CoA, which is obtained via the activation and conversion of fatty acids by acyl-CoA synthase (ACS). The first step in this process is the formation of lysophosphatidic acid (LPA) through the conversion of glycerol-3-phosphate and fatty acyl CoA, catalyzed by glycerol-3-phosphate acyltransferase (GPAT). The second step follows with the formation of phosphatidic acid, catalyzed by lysophosphatidic acid acyltransferase (LPAAT). Additionally, in certain enzyme reactions, different head groups are attached, generating different glycerophospholipids (127). During catabolism, GPLs are transformed into lysophospholipids (LPLs) and free fatty acids by the action of PLA₂ (128).

2.3.2 Altered glycerophospholipids profile in head and neck cancer

In a study conducted by Silen et al., which involved ten cases of OSCC patients, GPL metabolism was found to be mostly dysregulated, with phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositols (PI) being the most prominent lipid classes (16). However, in another study by Zhang et al., which included fifty cases of OSCC patients and fifty cases of corresponding healthy controls, all glycerophospholipids were found to be decreased, particularly PC and phosphoethanolamine plasmalogens (22). In addition, LysoPC (14:0) exhibited a stepwise decrease with the development and progression of OSCC (22). Considering the discrepancies between the two studies, further studies should be performed to involve larger sample sizes and proper controls. In the study of Jelonek et al., there was first a significant decrease followed by an increase in the levels of several PCs (PC34, PC36, and PC38 variants) and lysophosphatidylcholine (LPC16 and LPC18 variants) in HNC samples after radiotherapy (RT), in a radiation dose positively pattern (129). The precise changes within the glycerophospholipid profile require additional elucidation, and understanding the specific alteration pattern of these molecules could potentially serve as an indicator for radiotherapy effectiveness.

2.3.3 Dysregulated glycerophospholipids biosynthesis and catabolism in head and neck cancer

The PLA₂ superfamily, a key group of enzymes involved in glycerophospholipid catabolism, consists of over 30 different types of enzymes. These enzymes are categorized into six subfamilies, including cytosolic PLA₂s (cPLA₂s), calcium-independent PLA₂s (iPLA₂s), secreted PLA₂s (sPLA₂s), lysosomal PLA₂s, platelet-activating factor (PAF) acetylhydrolases, and adipose specific PLA_2s (130, 131). In general, PLA_2s are activated and upregulated in several human cancers (132–135). In a study involving five HNSCC patients, the metabolic profile was investigated using ¹H nuclear magnetic resonance (NMR) spectroscopy. The result revealed a significant elevation in the activity of PLA₂, especially cPLA₂, suggesting that PLA₂ may be a potential anti-cancer target of HNSCC (124). Additionally, in plasma level, Menschikowski et al. reported an increase in secretory phospholipase A₂ IIA (sPLA₂-IIA), which was significantly associated with shorter survival among HNC patients (136). Furthermore, Askari et al. observed constant activation of sPLA₂-IIA in OSCC tissues, and its negative correlation with the level of linoleic acid suggested that sPLA₂-IIA could serve as a possible indicator of lipid metabolism alteration in OSCC (137). Despite these findings, limited research exists on the regulation of glycerophospholipid synthesis-related enzymes in HNSCC.

2.4 Alteration of sphingolipids metabolism in head and neck cancer

Bioactive sphingolipids encompass important lipid molecules, including sphingosine, ceramide, sphingosine-1-phosphate (S1P), and ceramide-1-phosphate. These sphingolipids play a pivotal role in a multiple of biological processes such as cell mobility, proliferation, and survival (138, 139).

2.4.1 De novo biosynthesis and catabolism of sphingolipids

Ceramide is a central molecule in sphingolipid metabolism and could be formed by the condensation of serine and palmitoyl coenzyme A. The rate-limiting step in this process is catalyzed by the enzyme serine palmitoyltransferase (SPT) (140). Alternatively, ceramide can be generated by hydrolysis of complex sphingolipids via sphingomyelinase (SMases). Moreover, ceramide can be converted into sphingosine-1-phosphate (S1P) through the action of ceramidases (CDases) and sphingosine kinase 1 and 2 (SphK1and SphK2) (139, 140). Sphingomyelin synthase (SMS) takes phosphatidylcholine (PC) as a donor, inserting the choline group into ceramide as a head group, and converting ceramide to SM. Additionally, ceramide can be transformed into ceramide-1-phosphate (C1P) by the enzyme ceramide kinase (CERK). Furthermore, the metabolism of ceramides also gives rise to complex sphingolipids. As for the catabolism, ceramide is hydrolyzed by CDases, releasing free fatty acids and sphingosine (139, 140).

2.4.2 Altered sphingolipid profile in head and neck cancer

There is limited data available on changes in sphingolipid profiles in HNC. As reported by Ji et al., the concentration levels of sphingolipid 42:2 and 42:3 (SM 42:2 and SM 42:3) were significantly downregulated in laryngeal carcinoma patients when compared to those with laryngeal benign tumors and healthy controls (23).

Ceramide is one of the hub nodes in sphingolipid signaling. As reported by Ogretmen et al., the level of total ceramide was decreased in non-squamous head and neck cancers but increased in HNSCC tumor tissues. Interestingly, the level of C18-ceramide was unexpectedly lower in HNSCC (approximately 50% lower) (24). Increased of C18-ceramide by mammalian upstream regulator of growth and differentiation factor 1 (mUOG1) and mouse homologue of longevity assurance gene 1 (mLAG1), could inhibit the proliferation of HNSCC cells, possibly due to its modulation of telomerase activity and mitochondrial function (24). In accordance with the former study, Senkal et al. observed a low level of C18-ceramide and an upregulated level of C16-ceramide in HNC. Interestingly, C18-ceramide was proposed to have a pro-apoptotic function, whereas C16-ceramide exhibited a protective effect against ER stress and apoptosis (25). Similar decrease in ceramide was observed in laryngeal carcinoma and OSCC when compared with premalignant and normal controls (141–143). Clinically, HNSCC patients with reduced C18-ceramide in tumor tissues tended to have a higher incidence of lymphovascular invasion and lymph node metastasis, which consequently correlated with a higher overall stage of the primary tumor (144). Oppositely, Wang et al. reported that ceramides (d18:1/16:0 and d18:1/18:0) were significantly increased in OSCC patients and positively correlated with pathological stage (22).

Considering the critical functions of ceramide in cancer, more and more research is focusing on its role in cancer therapy. An in vitro study showed that ceramide enhanced paclitaxel-mediated apoptosis. A combination of paclitaxel and ceramide could rewire the cell cycle of HNSCC cells, eliminating cells from S and/or G2-M phases, indicating that this combination may offer an attractive alternative to conventional chemotherapy of HNSCC (145). L-reo-C6-Pyridineium-ceramide-bromide (L-t-C6-Pyr-Cer), a cationic water-soluble ceramide analogue, inhibited the growth of HNSCC cell lines with a low IC50. When combined with gemcitabine (GEM), it significantly prevented tumor growth of HNSCC in vivo. Moreover, the treatment effect of L-t-C6-Pyr-Cer/GMZ was 2.5 times more effective than that of 5-fluorouracil/cisplatin combination (146). Doxorubicin (DOX), an inducer of ceramide production, increased the level of C18-ceramide, inhibited cell growth, and induced cell death in HNSCC patients when combined with GEM (147). In addition, a phase II clinical study demonstrated that GEM/DOX treatment facilitated the chemotherapeutic efficacy in HNSCC patients who failed the first-line platinum therapy (148).

2.4.3 Dysregulated sphingolipids biosynthesis and catabolism in head and neck cancer

2.4.3.1 Sphingosine kinase 1

SphK1, a key enzyme participating in sphingosine-1-phosphate (S1P) synthesis, has been found to be consistently overexpressed in both HNSCC cell lines and primary tumors (149–151). Its expression was higher in HNSCC cells displaying a more invasive phenotype (152). The upregulation of SphK1 has been correlated with advanced tumor stages, lymph node involvement, recurrence of tumor, and poor survival in HNSCC (149, 150). Mechanistically, SphK1 promotes the invasive ability of human tongue squamous cell carcinoma by upregulating EGFR and STAT3 (152). What’s more, inhibition of SphK1 suppressed cell proliferation and enhanced the radiosensitivity of HNSCC cells (151, 153). In summary, SphK1 might function as an oncogene in HNSCC.

2.4.3.2 Acid ceramidase

Acid ceramidase is responsible for the degradation of ceramide within lysosomes (154). Overexpression of AC has been reported in a variety of human cancers, including HNSCC (155, 156). Interestingly, it is higher in HNSCC cell lines generated from metastasis tumor compared to those from primary tumor (157). As reported by Norris et al., overexpression of AC increased the resistance of HNSCC cells to Fas-induced apoptosis (155). Jang et al. found a negative correlation between AC expression and cisplatin sensitivity in head and neck cancer cells. Treatment with AC inhibitor N-oleoyl-ethanolamine (NOE) or genetic silencing of AC might be novel approaches to enhance cisplatin cytotoxicity (156). Moreover, Movila et al. reported that phosphoethanolamine dihydroceramide (PEDHC) derived from P. gingivalis downregulated the expression of AC, promoted the accumulation of ceramidase and inhibited the proliferation and migration of OSCC cell lines (158). Collectively, overexpression of AC facilitates the malignant behaviors of head and neck cancer cells, and it might be a potential target of head and neck cancer treatment.

2.5 Alteration of sterol lipids metabolism in head and neck cancer

Sterol lipids consist of various compounds, including sterols, steroids, secosteroids, bile acids, and others. Among sterols, there are cholesterol, ergosterol, stigmasterol, C24 propylsterol, etc. As the most prominent sterol lipid, cholesterol is widely distributed in mammalian cells. Functionally, sterol lipids are essential for cell membrane formation and participate in a diverse range of physiological and biological processes (159).

2.5.1 De novo biosynthesis and catabolism of sterol lipids

Taking cholesterol as an example, it is mainly synthesized via the mevalonate pathway, starting with acetyl-CoA and processing with the involvement of more than 20 enzymes. The major rate-limiting enzyme, 3-hydroxy-3-methylgrutaryl (HMG)–CoA reductase (HMGCR), transforms 3-hydroxy-3-methylgrutaryl (HMG-CoA) into mevalonate. Mevalonate is converted into farnesyl pyrophosphate (FPP), and two molecules of FPP are condensed to yield squalene. Squalene is then oxidized by squalene epoxidase (SQLE) to generate 2,3-epoxysqualene, lanolin alcohol, and cholesterol subsequently (91). Maintaining cellular cholesterol homeostasis is crucial for normal physiological processes. Excessive intracellular cholesterol is exported from cell by ATP-binding cassette (ABC) transporter to reduce intracellular cholesterol levels (160). As for its circulation, the cholesterol synthesized and obtained exogenously which is stored in the liver, is released into the bloodstream in the form of very-low-density lipoproteins (VLDLs). These VLDLs are converted into low-density lipoproteins (LDLs) and taken up by peripheral cells (161). Excessive circulating cholesterol would be transported to lipid-free or lipid-poor apolipoprotein A-I (apoA-I), leading to the production of high-density lipoproteins (HDLs) (162). Moreover, surplus cholesterol could be esterified by acyl coenzyme A-cholesterol acyltransferase (ACAT) to generate cholesteryl esters, which are stored in lipid droplets or circulated as plasma lipoproteins (163).

2.5.2 Dysregulated sterol lipids profile in head and neck cancer

Studies have shown that the serum level of total cholesterol (TC) in OSCC patients is significantly lower than those in healthy controls (21, 26, 27). In eleven HNC patients, Pereira et al. found a significant positive correlation between baseline LDL-cholesterol levels and changes in radiotherapy-induced carotid intima-media thickness, suggesting that LDL-cholesterol might serve as a predictor for RT-induced carotid atherosclerosis in HNC (28). A retrospective cohort study based on 4,575,818 individuals in Korea revealed that high TC and high LDL-cholesterol levels are protective factors and could reduce the risk of HNC (164). Additionally, a prospective analysis based on 474,929 participants from the UK biobank demonstrated a significant U-shaped association between HDL-C and HNC risk in males (29). Based on the 561,388 individuals of the Swedish AMORIS cohort, we found a positive association between blood levels of TC, apoA-I and the risk of HNC. Furthermore, HNSCC patients showed constantly higher levels of TC and apoA-I during the 30 years before diagnosis (30).

2.5.3 Dysregulated sterol lipids biosynthesis related enzymes in head and neck cancer

2.5.3.1 Sterol regulatory element-binding protein 2

As mentioned previously, SREBP2 plays a critical role in selectively modulating the transcription of genes encoding cholesterologenic enzymes (165). However, there’s limited research on SREBP2 in HNC. According to a study by Yang et al., SREBP2 was significantly downregulated in OSCC tissues and cell lines when compared with normal controls. Restoration of SREBP2 could inhibit cell proliferation, migration, invasion, and induce cell apoptosis in OSCC, suggesting its novel role as a tumor suppressor (166). Nevertheless, further research is needed to fully clarify the role of SREBP2 in HNC.

2.5.3.2 3-hydroxy-3-methylglutaryl–CoA reductase

HMGCR is the rate-limiting enzyme in the mevalonate pathway for cholesterol production. Several studies have found that the downregulation of HMGCR is associated with the progression of various tumors (167–169). Interestingly, the expression of HMGCR was found to be elevated in OSCC (170). Furthermore, additional analysis revealed an increased expression of HMGCR in radiation-resistant HNSCC cells (171).

Statin, an HMGCR inhibitor, is noted not only to decrease the level of cholesterol but also reduce the risk of HNSCC. Moreover, statin use has been linked to improved survival in HNSCC patients, particularly in those with HPV-positive tumors (172). In another study, it was proposed that statin use would facilitate the prognosis of HNC, leading to increased overall survival and cancer-specific survival at 2 years (173). What’s more, the application of atorvastatin reduced the rate of cisplatin-induced hearing loss by 19.7% without compromising the effectiveness of cisplatin treatment in HNC patients (174). However, a Mendelian randomization study proposed that the strategy of cholesterol-lowering in oral cancer and oropharyngeal cancer was confounded, warranting further investigation (175).

2.5.3.3 Squalene monooxygenase

SM, which is encoded by the SQLE gene, is the second rate-limiting enzyme in the process of cholesterol synthesis (3). In HNSCC, an elevated level of SQLE expression and gene amplification has been observed, promoting cell proliferation and correlating with the TNM stage of patients (176, 177). Moreover, a high level of SQLE mRNA expression was negatively associated with the survival of HNSCC patients (178). In addition, SQLE plays a role in the tumor microenvironment in HNSCC. It showed a negative correlation with the infiltration of CD8+ T cells, follicular helper T cells, regulatory T cells, and mast cells, while exhibiting a positive correlation with M0 macrophages and resting mast cells (177). Terbinafine, an inhibitor of SQLE clinically used as an antifungal reagent, has recently gained attention for its anti-cancer effects and is being extensively studied (178). In OSCC, terbinafine has been reported to inhibit the proliferation of cancer cells, possibly by suppressing Raf-MEK-ERK and stimulating the p21(cip1) - and p27(kip1) -associated signaling pathways (179, 180). However, further research is needed to fully understand its potential in treating HNSCC. Taken together, SQLE may serve as a novel biomarker for prognosis and a promising drug target for HNSCC.

2.5.3.4 Enhancer of zeste homolog 2

EZH2, a histone methyltransferase, plays a role in modulating endogenous cholesterol synthesis. It is highly expressed in HNSCC, and its upregulation has been found to be correlated with tumor aggressiveness and poor outcomes in HNSCC patients (181, 182). One of the possible mechanisms behind this correlation might lie in the hypermethylation of tumor suppressor genes induced by EZH2 (182). In addition, EZH2-mediated trimethylation modification of histone H3 lysine 27 directly regulates sterol regulatory element binding transcription factor 2 (SREBF2) and its target gene SQLE, which in turn influences the synthesis of endogenous cholesterol in HNSCC. Inhibition of EZH2 strongly activates genes related to cholesterol synthesis and rewrites cholesterol metabolism. As a result, DZNep, an EZH2 inhibitor, showed an impeded function in the proliferation and survival of the human hypopharynx carcinoma cell line FaDu (182). Furthermore, the effects of EZH2 inhibitors have been found to be enhanced following the inhibition of SQLE (178). Nonetheless, further study is needed to fully elucidate the mechanisms.

2.5.4 Dysregulated sterol lipids trafficking in head and neck cancer

2.5.4.1 Low-density lipoproteins receptor

The LDLR is responsible for trafficking of lipoprotein into cells. Increased level of LDLR has been detected in a variety of tumors, including pancreatic cancer (183), glioblastoma cancer (100), and breast cancer (184). However, the level of LDLR in HNSCC remains unreported. Meanwhile, a Mendelian randomization study suggested that LDLR variants decreased the risk of combined oral and oropharyngeal cancer via heritable reduction of LDL-C (175).

2.6 Alteration of prenol lipids, polyketides, saccharolipids metabolism in head and neck cancer

There have been no reports on the dysregulation of prenol lipids, polyketides, or saccharolipids in HNSCC to date, making them promising areas for further exploration.

3 Relationship between lipid metabolism and risk factors of head and neck cancer

3.1 Tobacco and alcohol consumption

Tobacco consumption is a well-established etiological factor in HNC (185, 186). Studies have consistently shown that HNSCC patients with a history of tobacco consumption have a significantly lower level of TC when compared with healthy individuals, especially those without a tobacco consumption history (18, 27, 187, 188). However, there’s no difference in serum levels of TC, LDL, VLDL, HDL, and triglyceride between oral cancer patients with and without tobacco consumption habit (189, 190). Interestingly, the level of serum HDL in oral cancer and oral precancer patients with habit of tobacco was decreased when compared to healthy controls with habit of tobacco use (189). Thus, tobacco carcinogens may increase the generation of free radicals and reactive oxygen species, leading to elevated oxidation/peroxidation rates of polyunsaturated fatty acids, which in turn affect the basic components of cell membranes and potentially be involved in the process of carcinogenesis (191).

Alcohol consumption is another established risk factor of HNC (192, 193). Prediagnosis alcohol intake has been associated with significantly poor overall survival in HNSCC patients in a dose-dependent pattern (194), which might be modified by the genetic polymorphisms of ADH1B and ALDH2 (195). Chronic excessive alcohol consumption is proposed to impair the effect of PPARα, which is involved in β-oxidation, disrupts the biosynthesis of cholesterol, and induces the accumulation of triglycerides (196).

3.2 Infection of human papillomaviruses

HPV infection has emerged as a hot spot in HNC research. HNSCC patients with different HPV infection status have different clinical outcomes (197, 198). Two virus oncoproteins, E6 and E7, contribute to the tumorigenic potential of HPV by inhibiting and degrading the tumor suppressor p53 and retinoblastoma-associated protein (pRB), respectively (199). What’s more, E6 stimulates hypoxia-inducible factor 1-α (HIF1α), leading to the activation of SREBP1, which, in turn, increases lipid synthesis by stimulating the expression of FASN and ACC. Additionally, HIF1 could promote the lipid uptake via upregulating receptor proteins from the CD36 family and FABPs (200). Moreover, E6 activates PI3K/Akt/mTOR pathways, resulting in the upregulation of downstream SREBP1 to mediate adipogenesis (201). The inactivation of Rb by E7 also activates the PI3K/Akt/mTOR pathway to promote adipogenesis (202). In HPV-positive HNSCC, a series of genes, such as PIK3CA, DDR2 or NF-kB, are found significantly mutated, contributing to the stimulation of glutamine and lipid metabolism (203–205). Meanwhile, HPV-negative HNSCC often exhibits inactivation of tumor suppressors, for example, p53, leading to the promotion of glycolysis (203–205).

3.3 High-fat diet and obesity

Unhealthy diet pattern disturbs the lipid metabolism and plays an important role in HNSCC. The consumption of fried meals, high-fat and processed meats, and sweets has been linked to an increased risk of laryngeal cancer (206–208). Specifically, the consumption of “unsaturated fats” and “animal unsaturated fatty acids” has been identified as risk factors for laryngeal carcinoma but protective factors for oral and pharyngeal cancer, as supported by references (209, 210). Intriguingly, different fat subtypes have been associated with the prognosis of HNSCC patients, impacting outcome factors such as recurrence and mortality. It was shown that high long-chain fatty acid (LCFA), unsaturated fatty acid, ω-3 PUFAs, and ω-6 PUFAs diet was significantly associated with a reduced risk of all-cause mortality, respectively (211). Additionally, a high intake of unsaturated fatty acid has been shown to reduce the specific mortality risk associated with HNSCC (211). Interestingly, it has been observed that a diet pattern with a low ω-6/ω-3 fatty acid ratio (ω-6/ω-3 = 2) suppressed carcinogenesis in the DMBA/BQE-induced hamster oral cancer model via inhibiting the expression of NF-κB p65, PCNA, and cyclin D1 (212).

Obesity, as one of the consequences of high-fat diet, is associated with an elevated incidence and impacts the overall survival of many human cancer types (213–216). In the complicated crosstalk between adipose tissue and cancer cells, mature adipocytes provide adipokines and lipids to cancer cells, while stromal and immune cells within adipose tissue release paracrine factors into the tumor microenvironment. Concurrently, the proliferation of cancer cells drives lipolysis in adipocytes (217). The possible mechanisms underpinning in the obesity-cancer link are proposed as: chronic inflammation in adipose tissue, oxidative stress, interplay between cancer cells and neighboring adipocytes, obesity-induced hypoxia, genetic susceptibility, immune response, and more (215).

However, the impact of obesity on head and neck cancer remains a subject of debate. There are some studies reported no significant association between body mass index (BMI) and the incidence of head and neck cancer (218, 219). In contrast, Dannenberg et al. reported that obesity was an independent risk factor for T1/2N0M0 OSCC patients, leading to poorer progression survival and disease-specific survival (220). In an in silico study, a combination of lipid metabolism-related genes, including TGFB1, SPP1, and SERPINE1, was proposed to be potential prognosis markers of OSCC patients (220, 221). Conversely, there are other studies showing that obesity was more likely to be a protective factor against the development of head and neck cancer (222–224). In a retrospective study, Gupta et al. brought out that being obese at the time of diagnosis of HNSCC (including oropharynx cancer, laryngeal carcinoma, and oral cancer patients; 72% of the patients were identified as stage IVA/B, and 28% identified as stage I-III), was an independent prognostic factor conferring better survival, suggesting extended time to recurrence, and better improvement of distant control (223). In a multinational case-control study conducted across nine countries, a low BMI was found to be associated with an increased risk of oral cancer. This conclusion remained consistent even after stratified analyses were performed (224). The underlying factors contributing to this contradiction might lie in the confounding variables such as age, alcohol and cigarette consumption, cancer stage, and treatment characteristics. A systemic review has summarized that obesity mechanically influences the levels and activities of lipid metabolism-related molecules (e.g., FFA, FAS, sPLA₂, FABP4, and FABP5), thereby contributing to the carcinogenesis and progression of head and neck cancer (225). Nonetheless, the precise mechanism through which obesity may reduce the risk of head and neck cancer remains elusive. In conclusion, further research is required to elucidate the relationship between obesity and head and neck cancer. And of importance, promoting a healthy diet and lifestyle should be emphasized in public health education for cancer prevention.

4 Conclusions

Lipid metabolism reprogram plays a critical role in the carcinogenesis and progression of head and neck cancer. In the present review, we have summarized the current understanding and advantages regarding the abnormal lipid metabolism profile, novel biomarkers, and possible mechanisms in head and neck cancer, according to the LIPID MAPS Lipid Classification System and cancer risk factors (Figure 2). We also discuss and emphasize their potential applications as biomarkers in the diagnosis, treatment and prognosis of head and neck cancer (Table 2).

Figure 2

Although significant advances have been made, as underscored in our review, there are still many unresolved scientific gaps demanding to be addressed. For instance, the roles of HSL, MCL, prenol lipids, polyketides, and saccharolipids in head and neck cancer need to be clarified. A more in-depth exploration of the related mechanisms is essential to shed light on the signaling crosstalk responsible for the alteration of lipid metabolism. The controversial roles of phosphatidylcholine, acetyl-CoA carboxylase, and especially obesity, remain to be elucidated. What’s more, there’s still an urgent need for the identification of novel therapeutic targets related to lipid metabolism.

In conclusion, a more profound understanding of lipid metabolism alterations and the intricacies of associated mechanisms will improve the accuracy of diagnosis, enable the customization of personalized treatments, and fine-tune prognosis strategies for individuals facing head and neck cancer.

References

• 1

  Beloribi-DjefafliaSVasseurSGuillaumondF. Lipid metabolic reprogramming in cancer cells. Oncogenesis (2016) 5(1):e189. doi: 10.1038/oncsis.2015.49

  • CrossRef
  • Google Scholar

• 2

  van MeerGVoelkerDRFeigensonGW. Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol (2008) 9(2):112–24. doi: 10.1038/nrm2330

  • CrossRef
  • Google Scholar

• 3

  BianXLiuRMengYXingDXuDLuZ. Lipid metabolism and cancer. J Exp Med (2021) 218(1):e20201606. doi: 10.1084/jem.20201606

  • CrossRef
  • Google Scholar

• 4

  SantosCRSchulzeA. Lipid metabolism in cancer. FEBS J (2012) 279(15):2610–23. doi: 10.1111/j.1742-4658.2012.08644.x

  • CrossRef
  • Google Scholar

• 5

  JohnsonDEBurtnessBLeemansCRLuiVWYBaumanJEGrandisJR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers (2020) 6(1):92. doi: 10.1038/s41572-020-00224-3

  • CrossRef
  • Google Scholar

• 6

  ChowLQM. Head and neck cancer. New Engl J Med (2020) 382(1):60–72. doi: 10.1056/NEJMra1715715

  • CrossRef
  • Google Scholar

• 7

  Wise-DraperTMDraperDJGutkindJSMolinoloAAWikenheiser-BrokampKAWellsSI. Future directions and treatment strategies for head and neck squamous cell carcinomas. Trans Res J Lab Clin Med (2012) 160(3):167–77. doi: 10.1016/j.trsl.2012.02.002

  • CrossRef
  • Google Scholar

• 8

  MuzaffarJBariSKirtaneKChungCH. Recent advances and future directions in clinical management of head and neck squamous cell carcinoma. Cancers (2021) 13(2):338. doi: 10.3390/cancers13020338

  • CrossRef
  • Google Scholar

• 9

  van HartenAMBrakenhoffRH. Targeted treatment of head and neck (Pre)Cancer: preclinical target identification and development of novel therapeutic applications. Cancers (2021) 13(11):2774. doi: 10.3390/cancers13112774

  • CrossRef
  • Google Scholar

• 10

  Halczy-KowalikLDrozdAStachowskaEDrozdRŻabskiTDomagałaW. Fatty acids distribution and content in oral squamous cell carcinoma tissue and its adjacent microenvironment. PloS One (2019) 14(6):e0218246. doi: 10.1371/journal.pone.0218246

  • CrossRef
  • Google Scholar

• 11

  SakuraiKTomiharaKYamazakiMHeshikiWMoniruzzamanRSekidoKet al. Cd36 expression on oral squamous cell carcinoma cells correlates with enhanced proliferation and migratory activity. Oral Dis (2020) 26(4):745–55. doi: 10.1111/odi.13210

  • CrossRef
  • Google Scholar

• 12

  UmaRSNareshKND'CruzAKMulherkarRBorgesAM. Metastasis of squamous cell carcinoma of the oral tongue is associated with down-regulation of epidermal fatty acid binding protein (E-fabp). Oral Oncol (2007) 43(1):27–32. doi: 10.1016/j.oraloncology.2005.12.024

  • CrossRef
  • Google Scholar

• 13

  SuYWLinYHPaiMHLoACLeeYCFangICet al. Association between phosphorylated amp-activated protein kinase and acetyl-coa carboxylase expression and outcome in patients with squamous cell carcinoma of the head and neck. PloS One (2014) 9(4):e96183. doi: 10.1371/journal.pone.0096183

  • CrossRef
  • Google Scholar

• 14

  KrontirasHRoyeGDBeenkenSEMyersRBMayoMSPetersGEet al. Fatty acid synthase expression is increased in neoplastic lesions of the oral tongue. Head Neck (1999) 21(4):325–9. doi: 10.1002/(sici)1097-0347(199907)21:4<325::aid-hed6>3.0.co;2-p

  • CrossRef
  • Google Scholar

• 15

  FahyESubramaniamSMurphyRCNishijimaMRaetzCRShimizuTet al. Update of the lipid maps comprehensive classification system for lipids. J Lipid Res (2009) 50 Suppl(Suppl):S9–14. doi: 10.1194/jlr.R800095-JLR200

  • CrossRef
  • Google Scholar

• 16

  DickinsonASaraswatMJoenvääräSAgarwalRJyllikoskiDWilkmanTet al. Mass spectrometry-based lipidomics of oral squamous cell carcinoma tissue reveals aberrant cholesterol and glycerophospholipid metabolism - a pilot study. Trans Oncol (2020) 13(10):100807. doi: 10.1016/j.tranon.2020.100807

  • CrossRef
  • Google Scholar

• 17

  ChristouCNTiblom EhrssonYLampaERisérusULaurellG. Circulating fatty acids in patients with head and neck cancer after treatment: an explorative study with a one-year perspective. Acta oto-laryngologica (2021) 141(9):878–84. doi: 10.1080/00016489.2021.1959950

  • CrossRef
  • Google Scholar

• 18

  PooreyVKThakurP. Alteration of lipid profile in patients with head and neck Malignancy. Indian J Otolaryngol Head Neck Surg Off Publ Assoc Otolaryngologists India (2016) 68(2):135–40. doi: 10.1007/s12070-015-0829-4

  • CrossRef
  • Google Scholar

• 19

  PatelPSShahMHJhaFPRavalGNRawalRMPatelMMet al. Alterations in plasma lipid profile patterns in head and neck cancer and oral precancerous conditions. Indian J Cancer (2004) 41(1):25–31. doi: 10.4103/0019-509X.12341

  • CrossRef
  • Google Scholar

• 20

  SomashekarBSKamarajanPDanciuTKapilaYLChinnaiyanAMRajendiranTMet al. Magic angle spinning nmr-based metabolic profiling of head and neck squamous cell carcinoma tissues. J Proteome Res (2011) 10(11):5232–41. doi: 10.1021/pr200800w

  • CrossRef
  • Google Scholar

• 21

  GargDSunilMKSinghPPSinglaNRaniSRKaurB. Serum lipid profile in oral precancer and cancer: A diagnostic or prognostic marker? J Int Oral Health JIOH (2014) 6(2):33–9.

  • Google Scholar

• 22

  WangLWangXLiYHouYSunFZhouSet al. Plasma lipid profiling and diagnostic biomarkers for oral squamous cell carcinoma. Oncotarget (2017) 8(54):92324–32. doi: 10.18632/oncotarget.21289

  • CrossRef
  • Google Scholar

• 23

  WangHLuoYChenHHouHHuQJiM. Non-targeted serum lipidomics analysis and potential biomarkers of laryngeal cancer based on uhplc-qtof-ms. Metabolites (2022) 12(11):1087. doi: 10.3390/metabo12111087

  • CrossRef
  • Google Scholar

• 24

  KoybasiSSenkalCESundararajKSpassievaSBielawskiJOstaWet al. Defects in cell growth regulation by C18:0-ceramide and longevity assurance gene 1 in human head and neck squamous cell carcinomas. J Biol Chem (2004) 279(43):44311–9. doi: 10.1074/jbc.M406920200

  • CrossRef
  • Google Scholar

• 25

  SenkalCEPonnusamySBielawskiJHannunYAOgretmenB. Antiapoptotic roles of ceramide-synthase-6-generated C16-ceramide via selective regulation of the atf6/chop arm of er-stress-response pathways. FASEB J Off Publ Fed Am Societies Exp Biol (2010) 24(1):296–308. doi: 10.1096/fj.09-135087

  • CrossRef
  • Google Scholar

• 26

  SherubinEJKannanKSKumarDNJosephI. Estimation of plasma lipids and its significance on histopathological grades in oral cancer: prognostic significance an original research. J Oral Maxillofac Pathol JOMFP (2013) 17(1):4–9. doi: 10.4103/0973-029x.110685

  • CrossRef
  • Google Scholar

• 27

  AcharyaSRaiPHallikeriKAnehosurVKaleJ. Serum lipid profile in oral squamous cell carcinoma: alterations and association with some clinicopathological parameters and tobacco use. Int J Oral Maxillofac Surg (2016) 45(6):713–20. doi: 10.1016/j.ijom.2016.01.015

  • CrossRef
  • Google Scholar

• 28

  PereiraEBGemignaniTSpositoACMatos-SouzaJRNadruzWJr. Low-density lipoprotein cholesterol and radiotherapy-induced carotid atherosclerosis in subjects with head and neck cancer. Radiat Oncol (London England) (2014) 9:134. doi: 10.1186/1748-717x-9-134

  • CrossRef
  • Google Scholar

• 29

  JiangHZhouLHeQJiangKYuanJHuangX. The effect of metabolic syndrome on head and neck cancer incidence risk: A population-based prospective cohort study. Cancer Metab (2021) 9(1):25. doi: 10.1186/s40170-021-00261-w

  • CrossRef
  • Google Scholar

• 30

  HuangYXiaoXSadeghiFFeychtingMHammarNFangFet al. Blood metabolic biomarkers and the risk of head and neck cancer: an epidemiological study in the swedish amoris cohort. Cancer Lett (2023) 557:216091. doi: 10.1016/j.canlet.2023.216091

  • CrossRef
  • Google Scholar

• 31

  KoundourosNPoulogiannisG. Reprogramming of fatty acid metabolism in cancer. Br J Cancer (2020) 122(1):4–22. doi: 10.1038/s41416-019-0650-z

  • CrossRef
  • Google Scholar

• 32

  CurrieESchulzeAZechnerRWaltherTCFareseRVJr. Cellular fatty acid metabolism and cancer. Cell Metab (2013) 18(2):153–61. doi: 10.1016/j.cmet.2013.05.017

  • CrossRef
  • Google Scholar

• 33

  KlapanIKatićVCuloFCukV. Prognostic significance of plasma prostaglandin E concentration in patients with head and neck cancer. J Cancer Res Clin Oncol (1992) 118(4):308–13. doi: 10.1007/bf01208621

  • CrossRef
  • Google Scholar

• 34

  MaYTemkinSMHawkridgeAMGuoCWangWWangXYet al. Fatty acid oxidation: an emerging facet of metabolic transformation in cancer. Cancer Lett (2018) 435:92–100. doi: 10.1016/j.canlet.2018.08.006

  • CrossRef
  • Google Scholar

• 35

  DruryJRychahouPGKelsonCOGeisenMEWuYHeDet al. Upregulation of cd36, a fatty acid translocase, promotes colorectal cancer metastasis by increasing mmp28 and decreasing E-cadherin expression. Cancers (2022) 14(1):252. doi: 10.3390/cancers14010252

  • CrossRef
  • Google Scholar

• 36

  WangJWenTLiZCheXGongLJiaoZet al. Cd36 upregulates dek transcription and promotes cell migration and invasion via gsk-3β/Β-catenin-mediated epithelial-to-mesenchymal transition in gastric cancer. Aging (2020) 13(2):1883–97. doi: 10.18632/aging.103985

  • CrossRef
  • Google Scholar

• 37

  JiangMWuNXuBChuYLiXSuSet al. Fatty acid-induced cd36 expression via O-glcnacylation drives gastric cancer metastasis. Theranostics (2019) 9(18):5359–73. doi: 10.7150/thno.34024

  • CrossRef
  • Google Scholar

• 38

  LuoXZhengEWeiLZengHQinHZhangXet al. The fatty acid receptor cd36 promotes hcc progression through activating src/pi3k/akt axis-dependent aerobic glycolysis. Cell Death Dis (2021) 12(4):328. doi: 10.1038/s41419-021-03596-w

  • CrossRef
  • Google Scholar

• 39

  AloiaAMüllhauptDChabbertCDEberhartTFlückiger-MangualSVukolicAet al. A fatty acid oxidation-dependent metabolic shift regulates the adaptation of braf-mutated melanoma to mapk inhibitors. Clin Cancer Res (2019) 25(22):6852–67. doi: 10.1158/1078-0432.Ccr-19-0253

  • CrossRef
  • Google Scholar

• 40

  WangJLiY. Cd36 tango in cancer: signaling pathways and functions. Theranostics (2019) 9(17):4893–908. doi: 10.7150/thno.36037

  • CrossRef
  • Google Scholar

• 41

  YangPQinHLiYXiaoAZhengEZengHet al. Cd36-mediated metabolic crosstalk between tumor cells and macrophages affects liver metastasis. Nat Commun (2022) 13(1):5782. doi: 10.1038/s41467-022-33349-y

  • CrossRef
  • Google Scholar

• 42

  AokiTKinoshitaJMunesueSHamabe-HoriikeTYamaguchiTNakamuraYet al. Hypoxia-induced cd36 expression in gastric cancer cells promotes peritoneal metastasis via fatty acid uptake. Ann Surg Oncol (2023) 30(5):3125–36. doi: 10.1245/s10434-022-12465-5

  • CrossRef
  • Google Scholar

• 43

  LigorioFDi CosimoSVerderioPCiniselliCMPizzamiglioSCastagnoliLet al. Predictive role of cd36 expression in her2-positive breast cancer patients receiving neoadjuvant trastuzumab. J Natl Cancer Institute (2022) 114(12):1720–7. doi: 10.1093/jnci/djac126

  • CrossRef
  • Google Scholar

• 44

  FengWWWilkinsOBangSUngMLiJAnJet al. Cd36-mediated metabolic rewiring of breast cancer cells promotes resistance to her2-targeted therapies. Cell Rep (2019) 29(11):3405–20.e5. doi: 10.1016/j.celrep.2019.11.008

  • CrossRef
  • Google Scholar

• 45

  PascualGAvgustinovaAMejettaSMartínMCastellanosAAttoliniCSet al. Targeting metastasis-initiating cells through the fatty acid receptor cd36. Nature (2017) 541(7635):41–5. doi: 10.1038/nature20791

  • CrossRef
  • Google Scholar

• 46

  HaidariSTröltzschMKnöselTLiokatisPKasintsovaAEberlMet al. Fatty acid receptor cd36 functions as a surrogate parameter for lymph node metastasis in oral squamous cell carcinoma. Cancers (2021) 13(16):4125. doi: 10.3390/cancers13164125

  • CrossRef
  • Google Scholar

• 47

  ScaliaAKindtNTrelcatANachtergaelADuezPJournéFet al. Development of a method for producing oxldl: characterization of their effects on hpv-positive head and neck cancer cells. Int J Mol Sci (2022) 23(20):12552. doi: 10.3390/ijms232012552

  • CrossRef
  • Google Scholar

• 48

  PascualGDomínguezDElosúa-BayesMBeckedorffFLaudannaCBigasCet al. Dietary palmitic acid promotes a prometastatic memory via schwann cells. Nature (2021) 599(7885):485–90. doi: 10.1038/s41586-021-04075-0

  • CrossRef
  • Google Scholar

• 49

  TaoLDingXYanLXuGZhangPJiAet al. Cd36 accelerates the progression of hepatocellular carcinoma by promoting fas absorption. Med Oncol (Northwood London England) (2022) 39(12):202. doi: 10.1007/s12032-022-01808-7

  • CrossRef
  • Google Scholar

• 50

  PanJFanZWangZDaiQXiangZYuanFet al. Cd36 mediates palmitate acid-induced metastasis of gastric cancer via akt/gsk-3β/Β-catenin pathway. J Exp Clin Cancer Res CR (2019) 38(1):52. doi: 10.1186/s13046-019-1049-7

  • CrossRef
  • Google Scholar

• 51

  O'SullivanSEKaczochaM. Fabp5 as a novel molecular target in prostate cancer. Drug Discovery Today (2020) 25(11):2056–61. doi: 10.1016/j.drudis.2020.09.018

  • CrossRef
  • Google Scholar

• 52

  LiuRZGodboutR. An amplified fatty acid-binding protein gene cluster in prostate cancer: emerging roles in lipid metabolism and metastasis. Cancers (2020) 12(12):3823. doi: 10.3390/cancers12123823

  • CrossRef
  • Google Scholar

• 53

  DumDOcokoljicALennartzMHube-MaggCReiswichVHöflmayerDet al. Fabp1 expression in human tumors: A tissue microarray study on 17,071 tumors. Virchows Archiv an Int J Pathol (2022) 481(6):945–61. doi: 10.1007/s00428-022-03394-5

  • CrossRef
  • Google Scholar

• 54

  PrayugoFBKaoTJAnuragaGTaHDKChuangJYLinLCet al. Expression profiles and prognostic value of fabps in colorectal adenocarcinomas. Biomedicines (2021) 9(10):1460. doi: 10.3390/biomedicines9101460

  • CrossRef
  • Google Scholar

• 55

  WuGXuYWangQLiJLiLHanCet al. Fabp5 is correlated with poor prognosis and promotes tumour cell growth and metastasis in clear cell renal cell carcinoma. Eur J Pharmacol (2019) 862:172637. doi: 10.1016/j.ejphar.2019.172637

  • CrossRef
  • Google Scholar

• 56

  RauchJAhlemannMSchaffrikMMackBErtongurSAndratschkeMet al. Allogenic antibody-mediated identification of head and neck cancer antigens. Biochem Biophys Res Commun (2004) 323(1):156–62. doi: 10.1016/j.bbrc.2004.08.071

  • CrossRef
  • Google Scholar

• 57

  MünzMZeidlerRGiresO. The tumour-associated antigen epcam upregulates the fatty acid binding protein E-fabp. Cancer Lett (2005) 225(1):151–7. doi: 10.1016/j.canlet.2004.11.048

  • CrossRef
  • Google Scholar

• 58

  FangLYWongTYChiangWFChenYL. Fatty-acid-binding protein 5 promotes cell proliferation and invasion in oral squamous cell carcinoma. J Oral Pathol Med Off Publ Int Assoc Oral Pathologists Am Acad Oral Pathol (2010) 39(4):342–8. doi: 10.1111/j.1600-0714.2009.00836.x

  • CrossRef
  • Google Scholar

• 59

  OhyamaYKawamotoYChibaTKikuchiKSakashitaHImaiK. Differential expression of fatty acid-binding proteins and pathological implications in the progression of tongue carcinoma. Mol Clin Oncol (2014) 2(1):19–25. doi: 10.3892/mco.2013.198

  • CrossRef
  • Google Scholar

• 60

  KimKH. Regulation of mammalian acetyl-coenzyme a carboxylase. Annu Rev Nutr (1997) 17:77–99. doi: 10.1146/annurev.nutr.17.1.77

  • CrossRef
  • Google Scholar

• 61

  ZuXZhongJLuoDTanJZhangQWuYet al. Chemical genetics of acetyl-coa carboxylases. Molecules (Basel Switzerland) (2013) 18(2):1704–19. doi: 10.3390/molecules18021704

  • CrossRef
  • Google Scholar

• 62

  BrusselmansKDe SchrijverEVerhoevenGSwinnenJV. Rna interference-mediated silencing of the acetyl-coa-carboxylase-alpha gene induces growth inhibition and apoptosis of prostate cancer cells. Cancer Res (2005) 65(15):6719–25. doi: 10.1158/0008-5472.Can-05-0571

  • CrossRef
  • Google Scholar

• 63

  ChajèsVCambotMMoreauKLenoirGMJoulinV. Acetyl-coa carboxylase alpha is essential to breast cancer cell survival. Cancer Res (2006) 66(10):5287–94. doi: 10.1158/0008-5472.Can-05-1489

  • CrossRef
  • Google Scholar

• 64

  LiKZhangCChenLWangPFangYZhuJet al. The role of acetyl-coa carboxylase2 in head and neck squamous cell carcinoma. PeerJ (2019) 7:e7037. doi: 10.7717/peerj.7037

  • CrossRef
  • Google Scholar

• 65

  LuoZSahaAKXiangXRudermanNB. Ampk, the metabolic syndrome and cancer. Trends Pharmacol Sci (2005) 26(2):69–76. doi: 10.1016/j.tips.2004.12.011

  • CrossRef
  • Google Scholar

• 66

  LiKChenLLinZZhuJFangYDuJet al. Role of the ampk/acc signaling pathway in trpp2-mediated head and neck cancer cell proliferation. BioMed Res Int (2020) 2020:4375075. doi: 10.1155/2020/4375075

  • CrossRef
  • Google Scholar

• 67

  LuoJHongYLuYQiuSChagantyBKZhangLet al. Acetyl-coa carboxylase rewires cancer metabolism to allow cancer cells to survive inhibition of the warburg effect by cetuximab. Cancer Lett (2017) 384:39–49. doi: 10.1016/j.canlet.2016.09.020

  • CrossRef
  • Google Scholar

• 68

  MenendezJALupuR. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer (2007) 7(10):763–77. doi: 10.1038/nrc2222

  • CrossRef
  • Google Scholar

• 69

  BandyopadhyaySPaiSKWatabeMGrossSCHirotaSHosobeSet al. Fas expression inversely correlates with pten level in prostate cancer and a pi 3-kinase inhibitor synergizes with fas sirna to induce apoptosis. Oncogene (2005) 24(34):5389–95. doi: 10.1038/sj.onc.1208555

  • CrossRef
  • Google Scholar

• 70

  OginoSNoshoKMeyerhardtJAKirknerGJChanATKawasakiTet al. Cohort study of fatty acid synthase expression and patient survival in colon cancer. J Clin Oncol (2008) 26(35):5713–20. doi: 10.1200/jco.2008.18.2675

  • CrossRef
  • Google Scholar

• 71

  HoriguchiAAsanoTAsanoTItoKSumitomoMHayakawaM. Fatty acid synthase over expression is an indicator of tumor aggressiveness and poor prognosis in renal cell carcinoma. J Urol (2008) 180(3):1137–40. doi: 10.1016/j.juro.2008.04.135

  • CrossRef
  • Google Scholar

• 72

  TakahiroTShinichiKToshimitsuS. Expression of fatty acid synthase as a prognostic indicator in soft tissue sarcomas. Clin Cancer Res (2003) 9(6):2204–12.

  • Google Scholar

• 73

  SebastianiVViscaPBottiCSanteusanioGGalatiGMPicciniVet al. Fatty acid synthase is a marker of increased risk of recurrence in endometrial carcinoma. Gynecologic Oncol (2004) 92(1):101–5. doi: 10.1016/j.ygyno.2003.10.027

  • CrossRef
  • Google Scholar

• 74

  AloPLViscaPMarciAMangoniABottiCDi TondoU. Expression of fatty acid synthase (Fas) as a predictor of recurrence in stage I breast carcinoma patients. Cancer (1996) 77(3):474–82. doi: 10.1002/(sici)1097-0142(19960201)77:3<474::Aid-cncr8>3.0.Co;2-k

  • CrossRef
  • Google Scholar

• 75

  SilvaSDAgostiniMNishimotoINColettaRDAlvesFALopesMAet al. Expression of fatty acid synthase, erbb2 and ki-67 in head and neck squamous cell carcinoma. A clinicopathological study. Oral Oncol (2004) 40(7):688–96. doi: 10.1016/j.oraloncology.2004.01.004

  • CrossRef
  • Google Scholar

• 76

  SilvaSDPerezDENishimotoINAlvesFAPintoCAKowalskiLPet al. Fatty acid synthase expression in squamous cell carcinoma of the tongue: clinicopathological findings. Oral Dis (2008) 14(4):376–82. doi: 10.1111/j.1601-0825.2007.01395.x

  • CrossRef
  • Google Scholar

• 77

  da SilvaSDCunhaIWNishimotoINSoaresFACarraroDMKowalskiLPet al. Clinicopathological significance of ubiquitin-specific protease 2a (Usp2a), fatty acid synthase (Fasn), and erbb2 expression in oral squamous cell carcinomas. Oral Oncol (2009) 45(10):e134–9. doi: 10.1016/j.oraloncology.2009.02.004

  • CrossRef
  • Google Scholar

• 78

  de AngelisCMde Lima-SouzaRAScariniJFEgalESAdo Amaral-SilvaGKde Oliveira GondakRet al. Immunohistochemical expression of fatty acid synthase (Fasn) is correlated to tumor aggressiveness and cellular differentiation in salivary gland carcinomas. Head Neck Pathol (2021) 15(4):1119–26. doi: 10.1007/s12105-021-01319-3

  • CrossRef
  • Google Scholar

• 79

  AgostiniMSilvaSDZecchinKGColettaRDJorgeJLodaMet al. Fatty acid synthase is required for the proliferation of human oral squamous carcinoma cells. Oral Oncol (2004) 40(7):728–35. doi: 10.1016/j.oraloncology.2004.01.011

  • CrossRef
  • Google Scholar

• 80

  SilvaSDCunhaIWYounesRNSoaresFAKowalskiLPGranerE. Erbb receptors and fatty acid synthase expression in aggressive head and neck squamous cell carcinomas. Oral Dis (2010) 16(8):774–80. doi: 10.1111/j.1601-0825.2010.01687.x

  • CrossRef
  • Google Scholar

• 81

  SilvaSDCunhaIWRangelALJorgeJZecchinKGAgostiniMet al. Differential expression of fatty acid synthase (Fas) and erbb2 in nonmalignant and Malignant oral keratinocytes. Virchows Archiv an Int J Pathol (2008) 453(1):57–67. doi: 10.1007/s00428-008-0626-5

  • CrossRef
  • Google Scholar

• 82

  AgostiniMAlmeidaLYBastosDCOrtegaRMMoreiraFSSeguinFet al. The fatty acid synthase inhibitor orlistat reduces the growth and metastasis of orthotopic tongue oral squamous cell carcinomas. Mol Cancer Ther (2014) 13(3):585–95. doi: 10.1158/1535-7163.Mct-12-1136

  • CrossRef
  • Google Scholar

• 83

  MimsJBansalNBharadwajMSChenXMolinaAJTsangAWet al. Energy metabolism in a matched model of radiation resistance for head and neck squamous cell cancer. Radiat Res (2015) 183(3):291–304. doi: 10.1667/rr13828.1

  • CrossRef
  • Google Scholar

• 84

  BoelckeWPTeixeiraIFAquinoIGMazzaroARCuadra-ZelayaFJMde SouzaAPet al. Pharmacological fatty acid synthase inhibitors differently affect the Malignant phenotype of oral cancer cells. Arch Oral Biol (2022) 135:105343. doi: 10.1016/j.archoralbio.2021.105343

  • CrossRef
  • Google Scholar

• 85

  AquinoIGBastosDCCuadra-ZelayaFJMTeixeiraIFSaloTColettaRDet al. Anticancer properties of the fatty acid synthase inhibitor tvb-3166 on oral squamous cell carcinoma cell lines. Arch Oral Biol (2020) 113:104707. doi: 10.1016/j.archoralbio.2020.104707

  • CrossRef
  • Google Scholar

• 86

  TesfayLPaulBTKonstorumADengZCoxAOLeeJet al. Stearoyl-coa desaturase 1 protects ovarian cancer cells from ferroptotic cell death. Cancer Res (2019) 79(20):5355–66. doi: 10.1158/0008-5472.Can-19-0369

  • CrossRef
  • Google Scholar

• 87

  MiyazakiMDobrzynAEliasPMNtambiJM. Stearoyl-coa desaturase-2 gene expression is required for lipid synthesis during early skin and liver development. Proc Natl Acad Sci United States America (2005) 102(35):12501–6. doi: 10.1073/pnas.0503132102

  • CrossRef
  • Google Scholar

• 88

  WangCShiMJiJCaiQZhaoQJiangJet al. Stearoyl-coa desaturase 1 (Scd1) facilitates the growth and anti-ferroptosis of gastric cancer cells and predicts poor prognosis of gastric cancer. Aging (2020) 12(15):15374–91. doi: 10.18632/aging.103598

  • CrossRef
  • Google Scholar

• 89

  MaXLSunYFWangBLShenMNZhouYChenJWet al. Sphere-forming culture enriches liver cancer stem cells and reveals stearoyl-coa desaturase 1 as a potential therapeutic target. BMC Cancer (2019) 19(1):760. doi: 10.1186/s12885-019-5963-z

  • CrossRef
  • Google Scholar

• 90

  LiaoCLiMLiXLiNZhaoXWangXet al. Trichothecin inhibits invasion and metastasis of colon carcinoma associating with scd-1-mediated metabolite alteration. Biochim Biophys Acta Mol Cell Biol Lipids (2020) 1865(2):158540. doi: 10.1016/j.bbalip.2019.158540

  • CrossRef
  • Google Scholar

• 91

  AbrahamMSowmyaSVRaoRSHaragannavarVCPatilSAugustineDet al. Stearoyl coenzyme A desaturase: A diagnostic and prognostic biomarker in patients with oral epithelial dysplasia and oral squamous cell carcinoma. Trans Res Oral Oncol (2018) 2057178X18782512. doi: 10.1177/2057178x18782512

  • CrossRef
  • Google Scholar

• 92

  NanjappaVRenuseSSatheGJRajaRSyedNRadhakrishnanAet al. Chronic exposure to chewing tobacco selects for overexpression of stearoyl-coa desaturase in normal oral keratinocytes. Cancer Biol Ther (2015) 16(11):1593–603. doi: 10.1080/15384047.2015.1078022

  • CrossRef
  • Google Scholar

• 93

  ZuXYZhangQHLiuJHCaoRXZhongJYiGHet al. Atp citrate lyase inhibitors as novel cancer therapeutic agents. Recent patents anti-cancer Drug Discovery (2012) 7(2):154–67. doi: 10.2174/157489212799972954

  • CrossRef
  • Google Scholar

• 94

  ZhouYBolluLRTozziFYeXBhattacharyaRGaoGet al. Atp citrate lyase mediates resistance of colorectal cancer cells to sn38. Mol Cancer Ther (2013) 12(12):2782–91. doi: 10.1158/1535-7163.Mct-13-0098

  • CrossRef
  • Google Scholar

• 95

  BecknerMEFellows-MayleWZhangZAgostinoNRKantJADayBWet al. Identification of atp citrate lyase as a positive regulator of glycolytic function in glioblastomas. Int J Cancer (2010) 126(10):2282–95. doi: 10.1002/ijc.24918

  • CrossRef
  • Google Scholar

• 96

  DaiMYangBChenJLiuFZhouYZhouYet al. Nuclear-translocation of acly induced by obesity-related factors enhances pyrimidine metabolism through regulating histone acetylation in endometrial cancer. Cancer Lett (2021) 513:36–49. doi: 10.1016/j.canlet.2021.04.024

  • CrossRef
  • Google Scholar

• 97

  MigitaTNaritaTNomuraKMiyagiEInazukaFMatsuuraMet al. Atp citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res (2008) 68(20):8547–54. doi: 10.1158/0008-5472.Can-08-1235

  • CrossRef
  • Google Scholar

• 98

  GöttgensELvan den HeuvelCNde JongMCKaandersJHLeendersWPAnsemsMet al. Acly (Atp citrate lyase) mediates radioresistance in head and neck squamous cell carcinomas and is a novel predictive radiotherapy biomarker. Cancers (2019) 11(12):1971. doi: 10.3390/cancers11121971

  • CrossRef
  • Google Scholar

• 99

  ZhengZQLiZXGuanJLLiuXLiJYChenYet al. Long noncoding rna tincr-mediated regulation of acetyl-coa metabolism promotes nasopharyngeal carcinoma progression and chemoresistance. Cancer Res (2020) 80(23):5174–88. doi: 10.1158/0008-5472.Can-19-3626

  • CrossRef
  • Google Scholar

• 100

  GuoDReinitzFYoussefMHongCNathansonDAkhavanDet al. An lxr agonist promotes glioblastoma cell death through inhibition of an egfr/akt/srebp-1/ldlr-dependent pathway. Cancer Discovery (2011) 1(5):442–56. doi: 10.1158/2159-8290.Cd-11-0102

  • CrossRef
  • Google Scholar

• 101

  EttingerSLSobelRWhitmoreTGAkbariMBradleyDRGleaveMEet al. Dysregulation of sterol response element-binding proteins and downstream effectors in prostate cancer during progression to androgen independence. Cancer Res (2004) 64(6):2212–21. doi: 10.1158/0008-5472.can-2148-2

  • CrossRef
  • Google Scholar

• 102

  BaoJZhuLZhuQSuJLiuMHuangW. Srebp-1 is an independent prognostic marker and promotes invasion and migration in breast cancer. Oncol Lett (2016) 12(4):2409–16. doi: 10.3892/ol.2016.4988

  • CrossRef
  • Google Scholar

• 103

  LiCYangWZhangJZhengXYaoYTuKet al. Srebp-1 has a prognostic role and contributes to invasion and metastasis in human hepatocellular carcinoma. Int J Mol Sci (2014) 15(5):7124–38. doi: 10.3390/ijms15057124

  • CrossRef
  • Google Scholar

• 104

  TiongTYWengPWWangCHSetiawanSAYadavVKPikatanNWet al. Targeting the srebp-1/hsa-mir-497/scap/fasn oncometabolic axis inhibits the cancer stem-like and chemoresistant phenotype of non-small cell lung carcinoma cells. Int J Mol Sci (2022) 23(13):7283. doi: 10.3390/ijms23137283

  • CrossRef
  • Google Scholar

• 105

  LiXChenYTJossonSMukhopadhyayNKKimJFreemanMRet al. Microrna-185 and 342 inhibit tumorigenicity and induce apoptosis through blockade of the srebp metabolic pathway in prostate cancer cells. PloS One (2013) 8(8):e70987. doi: 10.1371/journal.pone.0070987

  • CrossRef
  • Google Scholar

• 106

  LiLYYangQJiangYYYangWJiangYLiXet al. Interplay and cooperation between srebf1 and master transcription factors regulate lipid metabolism and tumor-promoting pathways in squamous cancer. Nat Commun (2021) 12(1):4362. doi: 10.1038/s41467-021-24656-x

  • CrossRef
  • Google Scholar

• 107

  TanMLinXChenHYeWYiJLiCet al. Sterol regulatory element binding transcription factor 1 promotes proliferation and migration in head and neck squamous cell carcinoma. PeerJ (2023) 11:e15203. doi: 10.7717/peerj.15203

  • CrossRef
  • Google Scholar

• 108

  FukudaMOgasawaraYHayashiHInoueKSakashitaH. Resveratrol inhibits proliferation and induces autophagy by blocking srebp1 expression in oral cancer cells. Molecules (Basel Switzerland) (2022) 27(23):8250. doi: 10.3390/molecules27238250

  • CrossRef
  • Google Scholar

• 109

  CarracedoACantleyLCPandolfiPP. Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer (2013) 13(4):227–32. doi: 10.1038/nrc3483

  • CrossRef
  • Google Scholar

• 110

  LiMXianHCTangYJLiangXHTangYL. Fatty acid oxidation: driver of lymph node metastasis. Cancer Cell Int (2021) 21(1):339. doi: 10.1186/s12935-021-02057-w

  • CrossRef
  • Google Scholar

• 111

  LuoXChengCTanZLiNTangMYangLet al. Emerging roles of lipid metabolism in cancer metastasis. Mol Cancer (2017) 16(1):76. doi: 10.1186/s12943-017-0646-3

  • CrossRef
  • Google Scholar

• 112

  SchlaepferIRRiderLRodriguesLUGijónMAPacCTRomeroLet al. Lipid catabolism via cpt1 as a therapeutic target for prostate cancer. Mol Cancer Ther (2014) 13(10):2361–71. doi: 10.1158/1535-7163.Mct-14-0183

  • CrossRef
  • Google Scholar

• 113

  TanZZouYZhuMLuoZWuTZhengCet al. Carnitine palmitoyl transferase 1a is a novel diagnostic and predictive biomarker for breast cancer. BMC Cancer (2021) 21(1):409. doi: 10.1186/s12885-021-08134-7

  • CrossRef
  • Google Scholar

• 114

  WangLLiCSongYYanZ. Inhibition of carnitine palmitoyl transferase 1a-induced fatty acid oxidation suppresses cell progression in gastric cancer. Arch Biochem biophysics (2020) 696:108664. doi: 10.1016/j.abb.2020.108664

  • CrossRef
  • Google Scholar

• 115

  XuAWangBFuJQinWYuTYangZet al. Diet-induced hepatic steatosis activates ras to promote hepatocarcinogenesis via cpt1α. Cancer Lett (2019) 442:40–52. doi: 10.1016/j.canlet.2018.10.024

  • CrossRef
  • Google Scholar

• 116

  QuQZengFLiuXWangQJDengF. Fatty acid oxidation and carnitine palmitoyltransferase I: emerging therapeutic targets in cancer. Cell Death Dis (2016) 7(5):e2226. doi: 10.1038/cddis.2016.132

  • CrossRef
  • Google Scholar

• 117

  MazzarelliPPucciSBonannoESestiFCalvaniMSpagnoliLG. Carnitine palmitoyltransferase I in human carcinomas: A novel role in histone deacetylation? Cancer Biol Ther (2007) 6(10):1606–13. doi: 10.4161/cbt.6.10.4742

  • CrossRef
  • Google Scholar

• 118

  Barros-FilhoMCReis-RosaLAHatakeyamaMMarchiFAChulamTScapulatempo-NetoCet al. Oncogenic drivers in 11q13 associated with prognosis and response to therapy in advanced oropharyngeal carcinomas. Oral Oncol (2018) 83:81–90. doi: 10.1016/j.oraloncology.2018.06.010

  • CrossRef
  • Google Scholar

• 119

  SuYWWuPSLinSHHuangWYKuoYSLinHP. Prognostic value of the overexpression of fatty acid metabolism-related enzymes in squamous cell carcinoma of the head and neck. Int J Mol Sci (2020) 21(18):6851. doi: 10.3390/ijms21186851

  • CrossRef
  • Google Scholar

• 120

  PrentkiMMadirajuSR. Glycerolipid metabolism and signaling in health and disease. Endocrine Rev (2008) 29(6):647–76. doi: 10.1210/er.2008-0007

  • CrossRef
  • Google Scholar

• 121

  ZechnerRZimmermannREichmannTOKohlweinSDHaemmerleGLassAet al. Fat signals–lipases and lipolysis in lipid metabolism and signaling. Cell Metab (2012) 15(3):279–91. doi: 10.1016/j.cmet.2011.12.018

  • CrossRef
  • Google Scholar

• 122

  LiuXLuYChenZLiuXHuWZhengLet al. The ubiquitin-specific peptidase usp18 promotes lipolysis, fatty acid oxidation, and lung cancer growth. Mol Cancer Res MCR (2021) 19(4):667–77. doi: 10.1158/1541-7786.Mcr-20-0579

  • CrossRef
  • Google Scholar

• 123

  IftikharRPenroseHMKingANSamudreJSCollinsMEHartonoABet al. Elevated atgl in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity. Oncogenesis (2021) 10(11):82. doi: 10.1038/s41389-021-00373-4

  • CrossRef
  • Google Scholar

• 124

  TripathiPKamarajanPSomashekarBSMacKinnonNChinnaiyanAMKapilaYLet al. Delineating metabolic signatures of head and neck squamous cell carcinoma: phospholipase A2, a potential therapeutic target. Int J Biochem Cell Biol (2012) 44(11):1852–61. doi: 10.1016/j.biocel.2012.06.025

  • CrossRef
  • Google Scholar

• 125

  ZhouXWeiJChenFXiaoXHuangTHeQet al. Epigenetic downregulation of the isg15-conjugating enzyme ubch8 impairs lipolysis and correlates with poor prognosis in nasopharyngeal carcinoma. Oncotarget (2015) 6(38):41077–91. doi: 10.18632/oncotarget.6218

  • CrossRef
  • Google Scholar

• 126

  ZhengSMatskovaLZhouXXiaoXHuangGZhangZet al. Downregulation of adipose triglyceride lipase by eb viral-encoded lmp2a links lipid accumulation to increased migration in nasopharyngeal carcinoma. Mol Oncol (2020) 14(12):3234–52. doi: 10.1002/1878-0261.12824

  • CrossRef
  • Google Scholar

• 127

  DolceVCappelloARLappanoRMaggioliniM. Glycerophospholipid synthesis as a novel drug target against cancer. Curr Mol Pharmacol (2011) 4(3):167–75. doi: 10.2174/1874467211104030167

  • CrossRef
  • Google Scholar

• 128

  MurakamiMSatoHTaketomiY. Updating phospholipase a(2) biology. Biomolecules (2020) 10(10):1457. doi: 10.3390/biom10101457

  • CrossRef
  • Google Scholar

• 129

  JelonekKPietrowskaMRosMZagdanskiASuchwalkoAPolanskaJet al. Radiation-induced changes in serum lipidome of head and neck cancer patients. Int J Mol Sci (2014) 15(4):6609–24. doi: 10.3390/ijms15046609

  • CrossRef
  • Google Scholar

• 130

  KitaYShindouHShimizuT. Cytosolic phospholipase a(2) and lysophospholipid acyltransferases. Biochim Biophys Acta Mol Cell Biol Lipids (2019) 1864(6):838–45. doi: 10.1016/j.bbalip.2018.08.006

  • CrossRef
  • Google Scholar

• 131

  PengZChangYFanJJiWSuC. Phospholipase A2 superfamily in cancer. Cancer Lett (2021) 497:165–77. doi: 10.1016/j.canlet.2020.10.021

  • CrossRef
  • Google Scholar

• 132

  DongQPatelMScottKFGrahamGGRussellPJSvedP. Oncogenic action of phospholipase A2 in prostate cancer. Cancer Lett (2006) 240(1):9–16. doi: 10.1016/j.canlet.2005.08.012

  • CrossRef
  • Google Scholar

• 133

  DenizotYChianéaTLabrousseFTruffinetVDelageMMathonnetM. Platelet-activating factor and human thyroid cancer. Eur J Endocrinol (2005) 153(1):31–40. doi: 10.1530/eje.1.01947

  • CrossRef
  • Google Scholar

• 134

  YamashitaSYamashitaJOgawaM. Overexpression of group ii phospholipase A2 in human breast cancer tissues is closely associated with their Malignant potency. Br J Cancer (1994) 69(6):1166–70. doi: 10.1038/bjc.1994.229

  • CrossRef
  • Google Scholar

• 135

  CaiQZhaoZAntalisCYanLDel PrioreGHamedAHet al. Elevated and secreted phospholipase a₂ Activities as new potential therapeutic targets in human epithelial ovarian cancer. FASEB J Off Publ Fed Am Societies Exp Biol (2012) 26(8):3306–20. doi: 10.1096/fj.12-207597

  • CrossRef
  • Google Scholar

• 136

  MenschikowskiMHagelgansASchulerUFroeschkeSRosnerASiegertG. Plasma levels of phospholipase A2-iia in patients with different types of Malignancies: prognosis and association with inflammatory and coagulation biomarkers. Pathol Oncol Res POR (2013) 19(4):839–46. doi: 10.1007/s12253-013-9652-y

  • CrossRef
  • Google Scholar

• 137

  AskariMDarabiMZare MahmudabadiROboodiatMFayeziSMostakhdemin HosseiniZet al. Tissue fatty acid composition and secretory phospholipase-A2 activity in oral squamous cell carcinoma. Clin Trans Oncol Off Publ Fed Spanish Oncol Societies Natl Cancer Institute Mexico (2015) 17(5):378–83. doi: 10.1007/s12094-014-1242-2

  • CrossRef
  • Google Scholar

• 138

  HannunYAObeidLM. Sphingolipids and their metabolism in physiology and disease. Nat Rev Mol Cell Biol (2018) 19(3):175–91. doi: 10.1038/nrm.2017.107

  • CrossRef
  • Google Scholar

• 139

  OgretmenB. Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer (2018) 18(1):33–50. doi: 10.1038/nrc.2017.96

  • CrossRef
  • Google Scholar

• 140

  van KruiningDLuoQvan Echten-DeckertGMielkeMMBowmanAEllisSet al. Sphingolipids as prognostic biomarkers of neurodegeneration, neuroinflammation, and psychiatric diseases and their emerging role in lipidomic investigation methods. Advanced Drug delivery Rev (2020) 159:232–44. doi: 10.1016/j.addr.2020.04.009

  • CrossRef
  • Google Scholar

• 141

  YuanYChiFWangSWangZ. Significance of ceramide and DNA ploidy in laryngeal carcinogenesis. ORL; J oto-rhino-laryngology its related specialties (2007) 69(5):283–8. doi: 10.1159/000103872

  • CrossRef
  • Google Scholar

• 142

  ChiFLYuanYSWangSYWangZM. Study on ceramide expression and DNA content in patients with healthy mucosa, leukoplakia, and carcinoma of the larynx. Arch otolaryngology–head Neck Surg (2004) 130(3):307–10. doi: 10.1001/archotol.130.3.307

  • CrossRef
  • Google Scholar

• 143

  YoungMRNevilleBWChiACLathersDMGillespieMBDayTA. Autocrine motility-stimulatory pathways of oral premalignant lesion cells. Clin Exp metastasis (2007) 24(2):131–9. doi: 10.1007/s10585-007-9063-0

  • CrossRef
  • Google Scholar

• 144

  KarahataySThomasKKoybasiSSenkalCEElojeimySLiuXet al. Clinical relevance of ceramide metabolism in the pathogenesis of human head and neck squamous cell carcinoma (Hnscc): attenuation of C(18)-ceramide in hnscc tumors correlates with lymphovascular invasion and nodal metastasis. Cancer Lett (2007) 256(1):101–11. doi: 10.1016/j.canlet.2007.06.003

  • CrossRef
  • Google Scholar

• 145

  MehtaSBlackintonDOmarIKouttabNMyrickDKlostergaardJet al. Combined cytotoxic action of paclitaxel and ceramide against the human tu138 head and neck squamous carcinoma cell line. Cancer chemotherapy Pharmacol (2000) 46(2):85–92. doi: 10.1007/s002800000140

  • CrossRef
  • Google Scholar

• 146

  SenkalCEPonnusamySRossiMJSundararajKSzulcZBielawskiJet al. Potent antitumor activity of a novel cationic pyridinium-ceramide alone or in combination with gemcitabine against human head and neck squamous cell carcinomas in vitro and in vivo. J Pharmacol Exp Ther (2006) 317(3):1188–99. doi: 10.1124/jpet.106.101949

  • CrossRef
  • Google Scholar

• 147

  SenkalCEPonnusamySRossiMJBialewskiJSinhaDJiangJCet al. Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas. Mol Cancer Ther (2007) 6(2):712–22. doi: 10.1158/1535-7163.Mct-06-0558

  • CrossRef
  • Google Scholar

• 148

  SaddoughiSAGarrett-MayerEChaudharyUO'BrienPEAfrinLBDayTAet al. Results of a phase ii trial of gemcitabine plus doxorubicin in patients with recurrent head and neck cancers: serum C₁₈-ceramide as a novel biomarker for monitoring response. Clin Cancer Res (2011) 17(18):6097–105. doi: 10.1158/1078-0432.Ccr-11-0930

  • CrossRef
  • Google Scholar

• 149

  FacchinettiMMGandiniNAFermentoMESterin-SpezialeNBJiYPatelVet al. The expression of sphingosine kinase-1 in head and neck carcinoma. Cells tissues organs (2010) 192(5):314–24. doi: 10.1159/000318173

  • CrossRef
  • Google Scholar

• 150

  ShiraiKKaneshiroTWadaMFuruyaHBielawskiJHannunYAet al. A role of sphingosine kinase 1 in head and neck carcinogenesis. Cancer Prev Res (Philadelphia Pa) (2011) 4(3):454–62. doi: 10.1158/1940-6207.Capr-10-0299

  • CrossRef
  • Google Scholar

• 151

  SinhaUKSchornVJHochstimCChinnSBZhuSMasoodR. Increased radiation sensitivity of head and neck squamous cell carcinoma with sphingosine kinase 1 inhibition. Head Neck (2011) 33(2):178–88. doi: 10.1002/hed.21418

  • CrossRef
  • Google Scholar

• 152

  TamashiroPMFuruyaHShimizuYKawamoriT. Sphingosine kinase 1 mediates head & Neck squamous cell carcinoma invasion through sphingosine 1-phosphate receptor 1. Cancer Cell Int (2014) 14(1):76. doi: 10.1186/s12935-014-0076-x

  • CrossRef
  • Google Scholar

• 153

  TamashiroPMFuruyaHShimizuYIinoKKawamoriT. The impact of sphingosine kinase-1 in head and neck cancer. Biomolecules (2013) 3(3):481–513. doi: 10.3390/biom3030481

  • CrossRef
  • Google Scholar

• 154

  CoantNSakamotoWMaoCHannunYA. Ceramidases, roles in sphingolipid metabolism and in health and disease. Adv Biol Regul (2017) 63:122–31. doi: 10.1016/j.jbior.2016.10.002

  • CrossRef
  • Google Scholar

• 155

  ElojeimySLiuXMcKillopJCEl-ZawahryAMHolmanDHChengJYet al. Role of acid ceramidase in resistance to fasl: therapeutic approaches based on acid ceramidase inhibitors and fasl gene therapy. Mol Ther J Am Soc Gene Ther (2007) 15(7):1259–63. doi: 10.1038/sj.mt.6300167

  • CrossRef
  • Google Scholar

• 156

  RohJLParkJYKimEHJangHJ. Targeting acid ceramidase sensitises head and neck cancer to cisplatin. Eur J Cancer (Oxford Engl 1990) (2016) 52:163–72. doi: 10.1016/j.ejca.2015.10.056

  • CrossRef
  • Google Scholar

• 157

  BeckhamTHElojeimySChengJCTurnerLSHoffmanSRNorrisJSet al. Targeting sphingolipid metabolism in head and neck cancer: rational therapeutic potentials. Expert Opin Ther Targets (2010) 14(5):529–39. doi: 10.1517/14728221003752768

  • CrossRef
  • Google Scholar

• 158

  YamadaCHoANusbaumAXuRDaveyMENicholsFet al. Inhibitory effect of porphyromonas gingivalis-derived phosphoethanolamine dihydroceramide on acid ceramidase expression in oral squamous cells. J Cell Mol Med (2023) 27(9):1290–5. doi: 10.1111/jcmm.17722

  • CrossRef
  • Google Scholar

• 159

  WollamJAntebiA. Sterol regulation of metabolism, homeostasis, and development. Annu Rev Biochem (2011) 80:885–916. doi: 10.1146/annurev-biochem-081308-165917

  • CrossRef
  • Google Scholar

• 160

  HuangBSongBLXuC. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nat Metab (2020) 2(2):132–41. doi: 10.1038/s42255-020-0174-0

  • CrossRef
  • Google Scholar

• 161

  GoldsteinJLBrownMS. The ldl receptor. Arteriosclerosis thrombosis Vasc Biol (2009) 29(4):431–8. doi: 10.1161/atvbaha.108.179564

  • CrossRef
  • Google Scholar

• 162

  PhillipsMC. Molecular mechanisms of cellular cholesterol efflux. J Biol Chem (2014) 289(35):24020–9. doi: 10.1074/jbc.R114.583658

  • CrossRef
  • Google Scholar

• 163

  ChangTYLiBLChangCCUranoY. Acyl-coenzyme A:Cholesterol acyltransferases. Am J Physiol Endocrinol Metab (2009) 297(1):E1–9. doi: 10.1152/ajpendo.90926.2008

  • CrossRef
  • Google Scholar

• 164

  ChoiSYCheongHKLeeMKKangJWLeeYCOhIHet al. Metabolic diseases and risk of head and neck cancer: A cohort study analyzing nationwide population-based data. Cancers (2022) 14(13):3277. doi: 10.3390/cancers14133277

  • CrossRef
  • Google Scholar

• 165

  BrownMSGoldsteinJL. The srebp pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell (1997) 89(3):331–40. doi: 10.1016/s0092-8674(00)80213-5

  • CrossRef
  • Google Scholar

• 166

  MingGLiWBi-ruZYue-hongSHong-yuY. Effect of srebp2 on proliferation and migration of oral squamous cell carcinoma and its regulatory mechanism. China J Oral Maxillofac Surg (2021) 19(4):295.

  • Google Scholar

• 167

  HuangJZhaoXLiXPengJYangWMiS. Hmgcr inhibition stabilizes the glycolytic enzyme pkm2 to support the growth of renal cell carcinoma. PloS Biol (2021) 19(4):e3001197. doi: 10.1371/journal.pbio.3001197

  • CrossRef
  • Google Scholar

• 168

  BengtssonENerjovajPWangefjordSNodinBEberhardJUhlénMet al. Hmg-coa reductase expression in primary colorectal cancer correlates with favourable clinicopathological characteristics and an improved clinical outcome. Diagn Pathol (2014) 9:78. doi: 10.1186/1746-1596-9-78

  • CrossRef
  • Google Scholar

• 169

  BrennanDJBrändstedtJRexhepajEFoleyMPonténFUhlénMet al. Tumour-specific hmg-coar is an independent predictor of recurrence free survival in epithelial ovarian cancer. BMC Cancer (2010) 10:125. doi: 10.1186/1471-2407-10-125

  • CrossRef
  • Google Scholar

• 170

  ChangJTWangHMChangKWChenWHWenMCHsuYMet al. Identification of differentially expressed genes in oral squamous cell carcinoma (Oscc): overexpression of npm, cdk1 and ndrg1 and underexpression of ches1. Int J Cancer (2005) 114(6):942–9. doi: 10.1002/ijc.20663

  • CrossRef
  • Google Scholar

• 171

  RiccoNFlorAWolfgeherDEfimovaEVRamamurthyAAppelbeOKet al. Mevalonate pathway activity as a determinant of radiation sensitivity in head and neck cancer. Mol Oncol (2019) 13(9):1927–43. doi: 10.1002/1878-0261.12535

  • CrossRef
  • Google Scholar

• 172

  GetzKRBellileEZarinsKRRullmanCChinnSBTaylorJMGet al. Statin use and head and neck squamous cell carcinoma outcomes. Int J Cancer (2020) 148(10):2440–8. doi: 10.1002/ijc.33441

  • CrossRef
  • Google Scholar

• 173

  GuptaAStokesWEguchiMHararahMAminiAMuellerAet al. Statin use associated with improved overall and cancer specific survival in patients with head and neck cancer. Oral Oncol (2019) 90:54–66. doi: 10.1016/j.oraloncology.2019.01.019

  • CrossRef
  • Google Scholar

• 174

  FernandezKAAllenPCampbellMPageBTownesTLiCMet al. Atorvastatin is associated with reduced cisplatin-induced hearing loss. J Clin Invest (2021) 131(1):e142616. doi: 10.1172/jci142616

  • CrossRef
  • Google Scholar

• 175

  GormleyMYarmolinskyJDuddingTBurrowsKMartinRMThomasSet al. Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A mendelian randomization study. PloS Genet (2021) 17(4):e1009525. doi: 10.1371/journal.pgen.1009525

  • CrossRef
  • Google Scholar

• 176

  LiJYangTWangQLiYWuHZhangMet al. Upregulation of sqle contributes to poor survival in head and neck squamous cell carcinoma. Int J Biol Sci (2022) 18(9):3576–91. doi: 10.7150/ijbs.68216

  • CrossRef
  • Google Scholar

• 177

  LiuYFangLLiuW. High sqle expression and gene amplification correlates with poor prognosis in head and neck squamous cell carcinoma. Cancer Manage Res (2021) 13:4709–23. doi: 10.2147/cmar.S305719

  • CrossRef
  • Google Scholar

• 178

  XuXChenJLiYYangXWangQWenYet al. Targeting epigenetic modulation of cholesterol synthesis as a therapeutic strategy for head and neck squamous cell carcinoma. Cell Death Dis (2021) 12(5):482. doi: 10.1038/s41419-021-03760-2

  • CrossRef
  • Google Scholar

• 179

  ChienMHLeeTSKaoCYangSFLeeWS. Terbinafine inhibits oral squamous cell carcinoma growth through anti-cancer cell proliferation and anti-angiogenesis. Mol carcinogenesis (2012) 51(5):389–99. doi: 10.1002/mc.20800

  • CrossRef
  • Google Scholar

• 180

  LiBLuLZhongMTanXXLiuCYGuoYet al. Terbinafine inhibits ksr1 and suppresses raf-mek-erk signaling in oral squamous cell carcinoma cells. Neoplasma (2013) 60(4):406–12. doi: 10.4149/neo_2013_052

  • CrossRef
  • Google Scholar

• 181

  NienstedtJCSchroederCClauditzTSimonRSauterGMuenscherAet al. Ezh2 overexpression in head and neck cancer is related to lymph node metastasis. J Oral Pathol Med (2018) 47(3):240–5. doi: 10.1111/jop.12673

  • CrossRef
  • Google Scholar

• 182

  MochizukiDMisawaYKawasakiHImaiAEndoSMimaMet al. Aberrant epigenetic regulation in head and neck cancer due to distinct ezh2 overexpression and DNA hypermethylation. Int J Mol Sci (2018) 19(12):3707. doi: 10.3390/ijms19123707

  • CrossRef
  • Google Scholar

• 183

  GuillaumondFBidautGOuaissiMServaisSGouirandVOlivaresOet al. Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. Proc Natl Acad Sci United States America (2015) 112(8):2473–8. doi: 10.1073/pnas.1421601112

  • CrossRef
  • Google Scholar

• 184

  de Gonzalo-CalvoDLópez-VilaróLNasarreLPerez-OlabarriaMVázquezTEscuinDet al. Intratumor cholesteryl ester accumulation is associated with human breast cancer proliferation and aggressive potential: A molecular and clinicopathological study. BMC Cancer (2015) 15:460. doi: 10.1186/s12885-015-1469-5

  • CrossRef
  • Google Scholar

• 185

  MirbodSMAhingSI. Tobacco-associated lesions of the oral cavity: part I. Nonmalignant lesions. J (Canadian Dental Association) (2000) 66(5):252–6.

  • Google Scholar

• 186

  MirbodSMAhingSI. Tobacco-associated lesions of the oral cavity: part ii. Malignant lesions. . J (Canadian Dental Association) (2000) 66(6):308–11.

  • Google Scholar

• 187

  KumarPAugustineJUrsABAroraSGuptaSMohantyVR. Serum lipid profile in oral cancer and leukoplakia: correlation with tobacco abuse and histological grading. J Cancer Res Ther (2012) 8(3):384–8. doi: 10.4103/0973-1482.103517

  • CrossRef
  • Google Scholar

• 188

  MohanSLCSatyanarayanaD. Altered serum lipids in the cases of head and neck cancer associated with the habit of tobacco consumption. Int J Otolaryngol Head Neck Surg (2017) 6(3):28–37. doi: 10.4236/ijohns.2017.63006

  • CrossRef
  • Google Scholar

• 189

  LoheVKDegwekarSSBhowateRRKaduRPDangoreSB. Evaluation of correlation of serum lipid profile in patients with oral cancer and precancer and its association with tobacco abuse. J Oral Pathol Med (2010) 39(2):141–8. doi: 10.1111/j.1600-0714.2009.00828.x

  • CrossRef
  • Google Scholar

• 190

  BanseriaNMalikRNigamRKTrichalVShrivastavaAJainRet al. Correlation of serum lipid profile, serum calcium, alkaline phosphatase and serum protein with histopathological grading and staging in head and neck cancer. J Evol Med Dent Sci (2014) 3:1978–86. doi: 10.14260/jemds/2014/2090

  • CrossRef
  • Google Scholar

• 191

  AmesBN. Dietary carcinogens and anticarcinogens. Oxygen radicals and degenerative diseases. Sci (New York NY) (1983) 221(4617):1256–64. doi: 10.1126/science.6351251

  • CrossRef
  • Google Scholar

• 192

  Di CredicoGPoleselJDal MasoLPauliFTorelliNLuceDet al. Alcohol drinking and head and neck cancer risk: the joint effect of intensity and duration. Br J Cancer (2020) 123(9):1456–63. doi: 10.1038/s41416-020-01031-z

  • CrossRef
  • Google Scholar

• 193

  KooHYHanKShinDWYooJEChoMHJeonKHet al. Alcohol drinking pattern and risk of head and neck cancer: A nationwide cohort study. Int J Environ Res Public Health (2021) 18(21);11204. doi: 10.3390/ijerph182111204

  • CrossRef
  • Google Scholar

• 194

  LeeWTHsiaoJROuCYHuangCCChangCCTsaiSTet al. The influence of prediagnosis alcohol consumption and the polymorphisms of ethanol-metabolizing genes on the survival of head and neck cancer patients. Cancer epidemiology Biomarkers Prev Publ Am Assoc Cancer Research cosponsored by Am Soc Prev Oncol (2019) 28(2):248–57. doi: 10.1158/1055-9965.Epi-18-0425

  • CrossRef
  • Google Scholar

• 195

  TsaiSTWongTYOuCYFangSYChenKCHsiaoJRet al. The interplay between alcohol consumption, oral hygiene, aldh2 and adh1b in the risk of head and neck cancer. Int J Cancer (2014) 135(10):2424–36. doi: 10.1002/ijc.28885

  • CrossRef
  • Google Scholar

• 196

  TomitaKAzumaTKitamuraNNishidaJTamiyaGOkaAet al. Pioglitazone Prevents Alcohol-Induced Fatty Liver in Rats through up-Regulation of C-Met. Gastroenterology (2004) 126(3):873–85. doi: 10.1053/j.gastro.2003.12.008

  • CrossRef
  • Google Scholar

• 197

  GrønhøjCJakobsenKKJensenDHRasmussenJAndersenEFriborgJet al. Pattern of and survival following loco-regional and distant recurrence in patients with hpv+ and hpv- oropharyngeal squamous cell carcinoma: A population-based study. Oral Oncol (2018) 83:127–33. doi: 10.1016/j.oraloncology.2018.06.012

  • CrossRef
  • Google Scholar

• 198

  AngKKHarrisJWheelerRWeberRRosenthalDINguyen-TânPFet al. Human papillomavirus and survival of patients with oropharyngeal cancer. New Engl J Med (2010) 363(1):24–35. doi: 10.1056/NEJMoa0912217

  • CrossRef
  • Google Scholar

• 199

  LeemansCRSnijdersPJFBrakenhoffRH. The molecular landscape of head and neck cancer. Nat Rev Cancer (2018) 18(5):269–82. doi: 10.1038/nrc.2018.11

  • CrossRef
  • Google Scholar

• 200

  SitarzKCzamaraKSzostekSKaczorA. The impact of hpv infection on human glycogen and lipid metabolism - a review. Biochim Biophys Acta Rev Cancer (2022) 1877(1):188646. doi: 10.1016/j.bbcan.2021.188646

  • CrossRef
  • Google Scholar

• 201

  YiJZhuJWuJThompsonCBJiangX. Oncogenic activation of pi3k-akt-mtor signaling suppresses ferroptosis via srebp-mediated lipogenesis. Proc Natl Acad Sci United States America (2020) 117(49):31189–97. doi: 10.1073/pnas.2017152117

  • CrossRef
  • Google Scholar

• 202

  MengesCWBagliaLALapointRMcCanceDJ. Human Papillomavirus Type 16 E7 up-Regulates Akt Activity through the Retinoblastoma Protein. Cancer Res (2006) 66(11):5555–9. doi: 10.1158/0008-5472.Can-06-0499

  • CrossRef
  • Google Scholar

• 203

  MauroCLeowSCAnsoERochaSThotakuraAKTornatoreLet al. Nf-Κb controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration. Nat Cell Biol (2011) 13(10):1272–9. doi: 10.1038/ncb2324

  • CrossRef
  • Google Scholar

• 204

  KawaiIMatsumuraHFujiiWNaitoKKusakabeKKisoYet al. Discoidin domain receptor 2 (Ddr2) regulates body size and fat metabolism in mice. Transgenic Res (2014) 23(1):165–75. doi: 10.1007/s11248-013-9751-2

  • CrossRef
  • Google Scholar

• 205

  HaoYSamuelsYLiQKrokowskiDGuanBJWangCet al. Oncogenic pik3ca mutations reprogram glutamine metabolism in colorectal cancer. Nat Commun (2016) 7:11971. doi: 10.1038/ncomms11971

  • CrossRef
  • Google Scholar

• 206

  BradshawPTSiega-RizAMCampbellMWeisslerMCFunkhouserWKOlshanAF. Associations between dietary patterns and head and neck cancer: the carolina head and neck cancer epidemiology study. Am J Epidemiol (2012) 175(12):1225–33. doi: 10.1093/aje/kwr468

  • CrossRef
  • Google Scholar

• 207

  EdefontiVHashibeMAmbrogiFParpinelMBraviFTalaminiRet al. Nutrient-based dietary patterns and the risk of head and neck cancer: A pooled analysis in the international head and neck cancer epidemiology consortium. Ann Oncol (2012) 23(7):1869–80. doi: 10.1093/annonc/mdr548

  • CrossRef
  • Google Scholar

• 208

  De VitoRLeeYCAParpinelMSerrainoDOlshanAFZevallosJPet al. Shared and study-specific dietary patterns and head and neck cancer risk in an international consortium. Epidemiol (Cambridge Mass) (2019) 30(1):93–102. doi: 10.1097/ede.0000000000000902

  • CrossRef
  • Google Scholar

• 209

  EdefontiVBraviFLa VecchiaCRandiGFerraroniMGaravelloWet al. Nutrient-based dietary patterns and the risk of oral and pharyngeal cancer. Oral Oncol (2010) 46(5):343–8. doi: 10.1016/j.oraloncology.2009.11.017

  • CrossRef
  • Google Scholar

• 210

  EdefontiVBraviFGaravelloWLa VecchiaCParpinelMFranceschiSet al. Nutrient-based dietary patterns and laryngeal cancer: evidence from an exploratory factor analysis. Cancer epidemiology Biomarkers Prev Publ Am Assoc Cancer Research cosponsored by Am Soc Prev Oncol (2010) 19(1):18–27. doi: 10.1158/1055-9965.Epi-09-0900

  • CrossRef
  • Google Scholar

• 211

  TahaHMRozekLSChenXLiZZarinsKRSladeANet al. Risk of disease recurrence and mortality varies by type of fat consumed before cancer treatment in a longitudinal cohort of head and neck squamous cell carcinoma patients. J Nutr (2022) 152(5):1298–305. doi: 10.1093/jn/nxac032

  • CrossRef
  • Google Scholar

• 212

  LeeHCLiangALinYHGuoYRHuangSY. Low dietary N-6/N-3 polyunsaturated fatty acid ratio prevents induced oral carcinoma in a hamster pouch model. Prostaglandins leukotrienes essential Fatty Acids (2018) 136:67–75. doi: 10.1016/j.plefa.2017.03.003

  • CrossRef
  • Google Scholar

• 213

  CalleEERodriguezCWalker-ThurmondKThunMJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. Adults. New Engl J Med (2003) 348(17):1625–38. doi: 10.1056/NEJMoa021423

  • CrossRef
  • Google Scholar

• 214

  HarveyAELashingerLMHurstingSD. The growing challenge of obesity and cancer: an inflammatory issue. Ann New York Acad Sci (2011) 1229:45–52. doi: 10.1111/j.1749-6632.2011.06096.x

  • CrossRef
  • Google Scholar

• 215

  De PergolaGSilvestrisF. Obesity as a major risk factor for cancer. J Obes (2013) 2013:291546. doi: 10.1155/2013/291546

  • CrossRef
  • Google Scholar

• 216

  HeQXiaBLiuALiMZhouZCheungECet al. Association of body composition with risk of overall and site-specific cancers: A population-based prospective cohort study. Int J Cancer (2021) 149(7):1435–47. doi: 10.1002/ijc.33697

  • CrossRef
  • Google Scholar

• 217

  LengyelEMakowskiLDiGiovanniJKoloninMG. Cancer as a matter of fat: the crosstalk between adipose tissue and tumors. Trends Cancer (2018) 4(5):374–84. doi: 10.1016/j.trecan.2018.03.004

  • CrossRef
  • Google Scholar

• 218

  GaudetMMPatelAVSunJHildebrandJSMcCulloughMLChenAYet al. Prospective studies of body mass index with head and neck cancer incidence and mortality. Cancer epidemiology Biomarkers Prev Publ Am Assoc Cancer Research cosponsored by Am Soc Prev Oncol (2012) 21(3):497–503. doi: 10.1158/1055-9965.Epi-11-0935

  • CrossRef
  • Google Scholar

• 219

  HashibeMHuntJWeiMBuysSGrenLLeeYC. Tobacco, alcohol, body mass index, physical activity, and the risk of head and neck cancer in the prostate, lung, colorectal, and ovarian (Plco) cohort. Head Neck (2013) 35(7):914–22. doi: 10.1002/hed.23052

  • CrossRef
  • Google Scholar

• 220

  IyengarNMKochharAMorrisPGMorrisLGZhouXKGhosseinRAet al. Impact of obesity on the survival of patients with early-stage squamous cell carcinoma of the oral tongue. Cancer (2014) 120(7):983–91. doi: 10.1002/cncr.28532

  • CrossRef
  • Google Scholar

• 221

  HuQPengJChenXLiHSongMChengBet al. Obesity and genes related to lipid metabolism predict poor survival in oral squamous cell carcinoma. Oral Oncol (2019) 89:14–22. doi: 10.1016/j.oraloncology.2018.12.006

  • CrossRef
  • Google Scholar

• 222

  FranceschiSDal MasoLLeviFContiETalaminiRLa VecchiaC. Leanness as early marker of cancer of the oral cavity and pharynx. Ann Oncol (2001) 12(3):331–6. doi: 10.1023/a:1011191809335

  • CrossRef
  • Google Scholar

• 223

  HicksDFBakstRDoucetteJKannBHMilesBGendenEet al. Impact of obesity on outcomes for patients with head and neck cancer. Oral Oncol (2018) 83:11–7. doi: 10.1016/j.oraloncology.2018.05.027

  • CrossRef
  • Google Scholar

• 224

  KreimerARRandiGHerreroRCastellsaguéXLa VecchiaCFranceschiS. Diet and body mass, and oral and oropharyngeal squamous cell carcinomas: analysis from the iarc multinational case-control study. Int J Cancer (2006) 118(9):2293–7. doi: 10.1002/ijc.21577

  • CrossRef
  • Google Scholar

• 225

  WangKYuXHTangYJTangYLLiangXH. Obesity: an emerging driver of head and neck cancer. Life Sci (2019) 233:116687. doi: 10.1016/j.lfs.2019.116687

  • CrossRef
  • Google Scholar