Editorial: Double-edged swords: Important factors connecting metabolic disorders and cancer development – from basic research to translational applications

COPYRIGHT © 2023 Kung, Barnoud, Yao and Murphy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Editorial PUBLISHED 02 March 2023 DOI 10.3389/fendo.2023.1168700


Editorial on the Research Topic
Double-edged swords: Important factors connecting metabolic disorders and cancer development -from basic research to translational applications The relationship between metabolic dysfunction and cancer development has been informed by research of epidemiology, endocrinology, cancer biology, chemistry, genomics, and metabolomics. By revealing both distinctive and shared mechanisms, the articles in this issue, including both original research studies and reviews, point to opportunities to discover new diagnostic and therapeutic strategies.
The relationship between metabolic syndromes (MetS) and cancer is multi-faceted (1). One field of interest is to link existing MetS with cancer prognosis. In "Effects of Metabolic Syndrome and Its Components on the Prognosis of Endometrial Cancer", Yang et al. explored the effects of MetS on the prognosis of endometrial cancer (EC) in over 500 patients, and found that combining high-density lipoprotein cholesterol with tumor stage and grade improved the prediction power for patient survival.
MetS also impacts other clinical outcomes in cancer patients.  They demonstrated that Mutp53 enhances fatty acid oxidation through dysregulating the miR-200c-ZEB2 axis to induce CPT1C, resulting in epithelial-mesenchymal transition phenotypes and increased cancer stemness. These data suggest that Mutp53driven metabolic reprogramming could be an effective therapeutic target. In a complementary Mini-Review article "p53-Mediated Indirect Regulation on Cellular Metabolism: From the Mechanism of Pathogenesis to the Development of Cancer Therapeutics", Wang and Chao summarized the indirect regulation of cellular metabolism by wild-type and mutant p53 through 1) transcriptional targets, 2) protein-protein interaction with other transcription factors, and 3) other signaling pathways. These findings support the premise that improving understanding of these mechanisms can inform novel therapeutic strategies through the concept of synthetic lethality.
One of the most studied cancer-regulating metabolic mechanisms is the Warburg effect, describing cancers' propensity to use glycolysis for their survival (4). In "FBP1/miR-24-1/enhancer axis activation blocks renal cell carcinoma progression via Warburg effect", Ju et al. showed that FBP1, a rate-limiting enzyme regulating gluconeogenesis and whose downregulation in renal cell carcinoma (RCC) is linked to poor survival, can be activated to slow down RCC progression. This can be achieved through employing miR-24-1, a nuclear activating miRNA, to activate FBP1 and repress the Warburg effect in RCC cells.
Metabolic alterations also regulate treatment response of cancer. In "Lapatinib Suppresses HER2-Overexpressed Cholangiocarcinoma and Overcomes ABCB1-Mediated Gemcitabine Chemoresistance", Bai et al. showed that HER2-targeting lapatinib overcomes gemcitabine resistance in cholangiocarcinoma (CCA). Gemcitabine works as a nucleoside analog to suppress cancer cell proliferation, and the authors showed that the active metabolite of gemcitabine, dFdCTP, is a substrate of ATP-binding cassette subfamily B member 1 (ABCB1). Gemcitabine-treated CCA cells develop a negative feedback loop by upregulating ABCB1 to cause gemcitabine resistance, which can be circumvented by the combination of lapatinib and gemcitabine.
The relationship between metabolism and tumorigenesis is more than one-directional. Oncogenes and tumor suppressors can also play important roles in the development of metabolic diseases (5,Chen et al.). In "Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity", Araujo et al. used both in vitro and in vivo models to show that another tumor suppressor, prostate apoptosis response-4 (Par-4), contributes to the development of obesity. Par-4 suppresses p53 and its target, complement factor c3, to regulate fat storage in adipocytes. Mice with Par-4 deletion developed obesity even with standard diet. Lower expression of Par-4 was found in obese patients and associated with increased risk of developing obesity later in life.
Finally, the microbiome can dictate our susceptibility to metabolic dysfunction and cancer (6). In "Connecting the Dots Between the Gut-IGF-1-Prostate Axis: A Role of IGF-1 in Prostate Carcinogenesis", Matsushita et al. summarized the relationship between prostate cancer (PCa) and Insulin-like growth factor 1 (IGF-1) to exemplify this concept. They highlighted the recent finding that short-chain fatty acids produced by the gut microbiota increase IGF-1 production, resulting in PCa progression through activation of downstream signaling pathways (7). They suggest that specialized dietary interventions could be implemented for prevention and treatment of PCa through optimizing the gut microbiome.
With fast-growing interest from scientific communities of different disciplines to understand the relationship between metabolic disorder and cancer development, this Research Topic hopefully serves as a precursor and medium to facilitate more nuanced, even provocative discussions to re-think and innovate actionable strategies to reduce the burden of human disease.

Author contributions
C-PK drafted the manuscript. C-PK, TB, C-HY, and MEM reviewed and revised the manuscript. All authors contributed to the article and approved the submitted version.
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