Wild-type and mutant p53 in cancer-related ferroptosis. A matter of stress management?

Abstract

Cancer cells within tumor masses are chronically exposed to stress caused by nutrient deprivation, oxygen limitation, and high metabolic demand. They also accumulate hundreds of mutations, potentially generating aberrant proteins that can induce proteotoxic stress. Finally, cancer cells are exposed to various damages during chemotherapy. In a growing tumor, transformed cells eventually adapt to these conditions, eluding the death-inducing outcomes of signaling cascades triggered by chronic stress. One such extreme outcome is ferroptosis, a form of iron-dependent non-apoptotic cell death mediated by lipid peroxidation. Not surprisingly, the tumor suppressor p53 is involved in this process, with evidence suggesting that it acts as a pro-ferroptotic factor and that its ferroptosis-inducing activity may be relevant for tumor suppression. Missense alterations of the TP53 gene are extremely frequent in human cancers and give rise to mutant p53 proteins (mutp53) that lose tumor suppressive function and can acquire powerful oncogenic activities. This suggests that p53 mutation provides a selective advantage during tumor progression, raising interesting questions on the impact of p53 mutant proteins in modulating the ferroptotic process. Here, we explore the role of p53 and its cancer-related mutants in ferroptosis, using a perspective centered on the resistance/sensitivity of cancer cells to exogenous and endogenous stress conditions that can trigger ferroptotic cell death. We speculate that an accurate molecular understanding of this particular axis may improve cancer treatment options.

Introduction

TP53 is possibly the most frequently altered gene in human cancers (Kandoth et al., 2013). The encoded p53 protein is a powerful tumor suppressor, and its loss-of-function is associated with cancer development and progression (Levine, 2020). Intriguingly, the majority of TP53 mutations are missense, encoding full-length proteins (mutp53) that are stably expressed in tumor cells. The pervasive retention of mutp53 in cancer suggests a selective advantage; indeed, missense p53 mutants have been reported to foster cancer cell proliferation, invasion, metastasis, and chemoresistance (Pilley et al., 2021; Dolma and Muller, 2022). Various oncogenic phenotypes and mechanisms of action, transcriptional and non-transcriptional, have been described for mutant p53 (Bellazzo et al., 2018; Kim and Lozano, 2018); nonetheless, our understanding of the real impact of mutp53 in cancer formation and progression remains incomplete.

An interesting hypothesis is that mutp53, similarly to its wild-type counterpart, may sense transformation-related cellular stresses and coordinate adaptive responses that help tumor progression (D’Orazi and Cirone, 2019; Mantovani et al., 2019). Such indirect action, dependent on multiple unpredictable circumstances, could explain why missense TP53 mutations are pervasively selected in tumors, but depletion of mutp53 in cancer cell lines and preclinical models gives variable and often contradictory results (Kennedy and Lowe, 2022; Wang et al., 2022).

Cancer cells within tumors experience multiple adverse conditions: nutrient and oxygen shortage, high metabolic demand, increased mutation rate, and chemotherapy-induced DNA damage. They eventually adapt to chronic stress, often hijacking stress-response pathways to favor homeostasis and survival. For instance, aberrant activation of the unfolded protein response can facilitate cancer progression by inducing epithelial mesenchymal transition, stimulating angiogenesis, and supporting tumor cell dormancy (Senft and Ronai, 2016; Limia et al., 2019). Some mechanisms by which mutp53 can help cancer cells adapt to cancer-related stress are beginning to emerge from tissue culture and animal models; characterizing such mechanisms may open new opportunities for targeted therapy.

Cancer-related stress conditions can directly or indirectly cause ferroptosis, a cell death process resulting from intracellular accumulation of lipid peroxides. Ferroptosis is under intense study due to its potential anti-cancer activity, especially in apoptosis-resistant tumors (Friedmann Angeli et al., 2019; Lei et al., 2022; Rodriguez et al., 2022). In fact, due to their altered metabolism, cancer cells are susceptible to ferroptosis and highly dependent on protective systems for survival; genes and pathways involved in such processes, therefore, could be targeted to improve chemotherapy. Not surprisingly, wild-type p53 has been reported to modulate ferroptosis in tumor models, possibly affecting response to treatment. The emerging relevance of the p53-ferroptosis axis inevitably raises important questions about the impact of cancer-associated mutant p53 in this phenomenon.

Ferroptosis

The term ‘ferroptosis’ describes a form of non-apoptotic cell death characterized by iron-dependent production of Lipid-ROS responsible for cell killing (Dixon et al., 2012). Since its first description, the number of papers studying ferroptosis has increased exponentially (Stockwell, 2022) confirming its involvement in both physiological and pathological events ranging from development, immune functions and tumor suppression, to neurodegeneration, autoimmunity and tumorigenesis (Jiang et al., 2021).

Lipid-ROS are the main executioners of ferroptosis, produced by intracellular iron accumulation, promoting peroxidation of PL-PUFA through Fenton reactions (Shah et al., 2018). The cellular labile iron pool required to stimulate ferroptosis can be the result of either increased iron import from the extracellular compartment, or released by autophagy-mediated degradation of ferritin (ferritinophagy) (Hou et al., 2016). Also iron-containing enzymes, such as ALOXs and POR, can promote lipid peroxidation, driving ferroptosis (Yang and Stockwell, 2016; Gagliardi et al., 2020; Zou et al., 2020).

On the other hand, biological processes protecting cells from Lipid-ROS must be concomitantly inhibited. GPX4 is the main intracellular factor responsible for Lipid-ROS reduction, using GSH as cofactor (Seiler et al., 2008). Thus, inhibition of GPX4 activity (e.g., through RSL3 administration), or impairment of GSH production through inhibition of the transmembrane glutamate/cystine antiporter “System Xc⁻”, will result in Lipid-ROS accumulation and ferroptosis (Dixon et al., 2012).

A key component of “System Xc⁻” is the solute transporter SLC7A11, frequently overexpressed in human malignancies, representing a potential target for ferroptosis-based therapies. In addition, Lipid-ROS can be detoxified by GPX4-independent factors such as FSP1 (Bersuker et al., 2019; Doll et al., 2019), DHODH (Mao et al., 2021), GCHI/BH4 (Kraft et al., 2020), and AKRs (Gagliardi et al., 2019; Gagliardi et al., 2020). The precise molecular mechanism(s) by which membrane-bound Lipid-ROS execute the death process remains unclear; one hypothesis is that they destabilize the plasma membrane structure, dysregulating its permeability (Figure 1).

FIGURE 1

P53 behaves primarily as a pro-ferroptotic factor, since it negatively regulates SLC7A11, increasing sensitivity to ferroptosis (Jiang et al., 2015b). P53 also controls the expression of enzymes involved in polyamine, glutamine, and iron metabolism, facilitating cell death by ferroptosis inducers. Importantly, using mouse models, the pro-ferroptotic activity of p53 was elegantly demonstrated to be sufficient for tumor suppression in vivo (Wang et al., 2016). Under certain conditions, however, p53 can also inhibit ferroptosis facilitating ROS detoxification and lipid homeostasis, limiting their pro-oncogenic action (Liu et al., 2020; Liu and Gu, 2022b).

Less is known on the impact of mutant p53 in the ferroptotic process. The consensus is that it increases sensitivity to ferroptosis, since mutp53 efficiently represses SLC7A11 (Gnanapradeepan et al., 2018; Magri et al., 2021). However, there is contradictory evidence. For instance, the drug APR-246 can induce ferroptosis more efficiently in blood cancer cells with mutp53 (Birsen et al., 2021; Fujihara et al., 2022; Hong et al., 2022). Although the pro-ferroptotic action of APR-246 is independent of p53 (Liu et al., 2017; Magri et al., 2021; Fujihara et al., 2022), the drug is a powerful inhibitor of mutant p53 (Hassin and Oren, 2022; Levine, 2022), and this may contribute to its efficacy. Similarly, the quinolinol MMRi62 was shown to induce ferroptosis in pancreatic cancer cells by inducing ferritinophagy (see below), but also by mutp53 destabilization (Li et al., 2022). Thus, we speculate that mutant p53 can modulate the sensitivity of cancer cells to ferroptosis not only directly, e.g., controlling ferroptotic genes, but also indirectly, by facilitating cellular adaptation to cancer-related stress.

p53 and stress conditions triggering ferroptosis

Hypoxia

Hypoxia is chronic in most tumors, and this condition is often exploited by cancer cells to sustain proliferation, metabolism, tumor invasion, and metastasis (Yang et al., 2020). In this context, a key role is played by HIF1, a transcription factor activated by low oxygen and frequently overexpressed in cancer (Su et al., 2022). Interestingly, HIF1 inhibits ferroptosis by: i) upregulating SCD1 to increase MUFA synthesis; ii) inhibiting the expression of ACSL4 to reduce Lipid-ROS generation, and iii) inhibiting the degradation of SLC7A11 (Su et al., 2022). Therefore, the reduced efficacy of radiation or drug-based therapies in solid tumors has been, at least in part, associated with HIF1-mediated inhibition of ferroptosis (Wang et al., 2019; Su et al., 2022).

p53 is activated by hypoxia, driving a cellular response that also involves modulation of cell metabolism (Liu and Gu, 2022a). In particular, p53 has a complex relationship with HIF1ɑ. The two proteins interact, and both wild-type and mutp53 potentiate the transcriptional activity of HIF1ɑ (Sermeus and Michiels, 2011; Eriksson et al., 2019). Reciprocally, activated HIF1ɑ stimulates p53 expression by binding to its promoter (Madan et al., 2019). Such positive feedback may be relevant for aberrant accumulation of highly stable mutp53 proteins in hypoxic cancer cells. In turn, mutp53 interacts with HIF1ɑ, stabilizing it, and promoting its DNA binding, increasing expression of genes that contribute to hypoxia-induced cell growth and survival (Madan et al., 2019). Mutant p53 can enhance angiogenesis by HIF1/VEGF signaling, and many HIF1-target genes are also targets of NRF2, linking hypoxic response to redox homeostasis (Eriksson et al., 2019). It would be interesting to establish to what extent the interaction of mutp53 with HIF1ɑ contributes to determine the sensitivity to ferroptosis of hypoxic cancer cells. Of note, mutp53/HIF1ɑ complexes drive expression of miR-30d, that reshapes the structure of Golgi apparatus, promoting cancer cells secretory activity. This impacts on the tumor microenvironment, with implications for hormonal and mechanical signaling pathways (Capaci et al., 2020), but also affects ER homeostasis and UPR signaling that may affect ferroptosis (see below).

Oxidative stress

ROS production is associated with both physiological and pathological conditions. Proper ROS production contributes to differentiation, immunity, and cell signaling, but uncontrolled accumulation leads to damage of proteins, lipids, and nucleic acids, causing “oxidative stress”, involved in cardiovascular and neurodegenerative diseases, obesity, aging, and cancer (Pizzino et al., 2017; Szewczyk-Golec et al., 2018).

Oxidative DNA damage is one of the stimuli driving tumorigenesis (Pizzino et al., 2017), and was detected in cells dying through ferroptosis (Erlanson et al., 2019; Liu J. et al., 2021). Therefore, in addition to being an integral part of the molecular mechanism of ferroptotic death, oxidative stress might regulate the process itself (Liu J. et al., 2021).

p53 is activated by oxidative stress, and can reduce ROS to promote cell survival, or increase ROS to facilitate cell death, depending on its gene targets or binding partners (Eriksson et al., 2019). The cellular response to oxidative stress is mainly regulated by NRF2, a transcription factor that controls expression of several antioxidant proteins (Rojo de la Vega et al., 2018). Notably, depending on cellular context, p53 can increase NRF2 levels by preventing its degradation, or reduce NRF2 levels by repressing its transcription (Eriksson et al., 2019; Liu and Gu, 2022a). Oncogenic mutp53 apparently has opposite effects. For instance, in lung and breast epithelial cells wt p53 suppressed NOX4 reducing ROS levels and cell migration, while mutp53 was shown to stimulate ROS production and metastasis (Boudreau et al., 2014). Mutp53 binds NRF2 on the SLC7A11 promoter, repressing transcription; this renders mutant p53 cells more sensitive to oxidative assaults and prone to ferroptosis (Liu et al., 2017). However, in breast cancer models, mutant p53 cooperates with NRF2 to transcribe proteasome components, alleviating proteotoxic stress and enhancing cell survival and cancer aggressiveness (Walerych et al., 2016; Lisek et al., 2018). Intriguingly, expression of transactivation-defective p53(3K), or ROS generation alone, could not induce ferroptosis, but their combination induced massive ferroptotic cell death (Jiang et al., 2015a; Jiang et al., 2015b); this indicates that p53-dependent ferroptosis may be a crucial tumor-suppressive response to oxidative stress. Similarly, the deacetylase SIRT3 represses p53-mediated ferroptosis in various cancer cells (Jin et al., 2021). SIRT3 expression is altered in several tumors (Chen et al., 2014; Ansari et al., 2017), and may cooperate with p53 mutation to increase cancer cell resistance to ferroptosis upon oxidative stress.

Oxidative stress can also trigger ferroptosis by enhancing peroxidation of membrane lipids. Interestingly, p53 can upregulate iPLA2β, a Ca-independent phospholipase that cleaves oxidized fatty acids, promoting their cytosolic detoxification, and thus limiting ferroptosis. Notably, p53 upregulates iPLA2β only under conditions of moderate lipid damage, facilitating adaptation to oxidative stress (Chen et al., 2021; Liu and Gu, 2022b). Loss of p53 function would cut this modulatory feedback, sensitizing p53-null cancer cells to ROS-induced lipid damage. Cells with oncogenic p53 mutations also lack this adaptive circuit, but may compensate with enhanced activity of NRF2 (see above).

Endoplasmic reticulum stress

Nutrient deprivation, proteasome dysfunction, sustained secretory activity, and somatic mutations in ER client proteins cause dysregulated proteostasis in proliferating tumor cells, thus triggering activation of the unfolded protein response (UPR) (Corazzari et al., 2017; Chen and Cubillos-Ruiz, 2021). Accumulation of unfolded/misfolded proteins in the ER is sensed by the receptors PERK, IRE1, and ATF6, that trigger activation/upregulation of transcription factors: ATF4, induced by PERK activation, XBP1s, produced by IRE1-dependent cytoplasmic splicing of XBP1 mRNA, and ATF6f, generated by proteolytic cleavage of activated ATF6. These factors orchestrate a transcriptional response aimed to: i) increase ER folding capacity; ii) inhibit cap-dependent translation; iii) degrade misfolded/unfolded ER client proteins (ERAD). Overall these activities sustain cell survival (“adaptation phase” of UPR), but acute or unresolved ER stress stimulates apoptosis (“cell death phase”) (Pagliarini et al., 2015; Corazzari et al., 2017). A potential link between ER stress and ferroptosis has been proposed due to the identification of CHAC1 as a ferroptotic marker (Dixon et al., 2014); indeed CHAC1 is upregulated upon ER stress and contributes to GSH degradation (Galluzzi et al., 2012), thus connecting the two pathways (Dixon et al., 2014). However, we observed that UPR is not required for ferroptosis in metastatic melanoma cells, despite a clear and early upregulation of CHAC1, that could be be abrogated by inhibiting NRF2, suggesting that CHAC1 is under control of both UPR and NRF2 (Gagliardi et al., 2019; Gagliardi et al., 2020). Clearly, further studies are required to unveil the real involvement of ER stress in ferroptosis.

Evidence linking wt p53 to ER stress is scarce, but various observations implicate mutant p53 in protein homeostasis. First, mutp53 cooperates with NRF2 to upregulate proteasome components, thus increasing protein turnover in cancer cells (Walerych et al., 2016; Lisek et al., 2018). This accelerates degradation of tumor-suppressors, promoting cell proliferation; at the same time it can help reduce or resolve ER stress, promoting cell survival. Second, mutp53 enhances expression of ENTPD5, an ER enzyme involved in folding of N-glycosylated proteins (Vogiatzi et al., 2016). This facilitates the maturation and secretion of growth-factor receptors, promoting cell proliferation; it may also alleviate ER stress by enhancing protein folding. Third, mutp53 induces Golgi remodeling and increases protein secretion; this could alter ER protein homeostasis and favor adaptation to ER stress (Capaci et al., 2020). Finally, we found that mutp53 protects cancer cells from drug-induced ER stress by modulating the UPR, in particular by enhancing activation of ATF6 (Sicari et al., 2019). Although the impact of ER stress in ferroptosis remains to be defined, it is conceivable that alterations in p53 function may affect sensitivity to ferroptosis at least in part by modulating protein homeostasis and the UPR.

Nutrient deprivation and autophagy

Autophagy is an evolutionarily-conserved process responsible for lysosomal degradation of intracellular cargoes, sustaining cell survival under nutrient shortage conditions (Corazzari et al., 2013). Autophagy plays a paradoxical role in tumorigenesis, depending on the stage of tumor development; it is suppressive in early stages, mainly through degradation of potentially oncogenic molecules, but becomes oncogenic in advanced stages, promoting cell survival and ameliorating stress in the microenvironment (Galluzzi et al., 2015). Evidence of autophagy has been detected in cancer cells dying by ferroptosis, suggesting a potential connection between the two pathways (Liu L. et al., 2021). Indeed, NCOA4 mediates autophagy-dependent degradation of FTH, thus releasing iron (ferritinophagy) and triggering lipid peroxidation and ferroptosis (Mancias et al., 2014). Recently, other factors linking ferroptosis to specific autophagic processes have been identified, in particular affecting Lipid-ROS generation: for instance RAB7A (lipophagy) (Bai et al., 2019), ARNTL (clockophagy) (Yang et al., 2019), and HSP90/HSC70 (CMA) (Wu et al., 2019). In fact, it has been suggested that ferroptosis may be considered an autophagy-based type of cell death (Zhou et al., 2020), although this concept is still debated.

Wild-type p53 modulates autophagy both directly and indirectly (Maiuri et al., 2010; D’Orazi and Cirone, 2019; Liu and Gu, 2022a). When activated by DNA-damage, nuclear p53 upregulates autophagy-associated genes, contributing to cancer cell death upon chemotherapy (Broz and Attardi, 2013). In contrast, cytoplasmic/mitochondrial p53 can suppress autophagy (Green and Kroemer, 2009). Additionally, p53 controls autophagy via interaction with key metabolic pathways, for instance positively modulating AMPK activity and negatively regulating AKT and mTOR (Mrakovcic and Fröhlich, 2018; Liu and Gu, 2022a).

Tumor-associated p53 mutants cannot transactivate autophagy genes and may acquire a suppressive role in autophagy (Cordani et al., 2017; Shi et al., 2021); especially mutp53 proteins with a pervasive cytoplasmic localization (Morselli et al., 2008). Mutp53 can also bind and inhibit AMPK (Zhou et al., 2014), and promote mTOR activation, indirectly suppressing autophagy (Liu and Gu, 2022a). So, although autophagy can help cancer cells overcome nutrient stress, evidence indicates that mutp53 inhibits autophagy to foster cancer aggressiveness. It is plausible that the p53 status may determine the sensitivity of cancer cells to ferroptosis also by modulating stress-induced autophagy.

Conclusion

Although cancer-related stress originates from a relatively small number of conditions—nutrient imbalance, hypoxia, reactive oxygen or nitrogen compounds, DNA damage, somatic mutations—the multiple pathways involved and the variable conditions that a tumor experiences during its clinical evolution generate an extremely complex scenario. Within this framework, the p53 pathway plays a central role in the response to stress, in particular determining whether cancer cells adapt or succumb to it via regulated cell death—including ferroptosis (Figure 2).

FIGURE 2

We suggest that mutant p53 can provide a selective advantage to tumors by facilitating adaptation to stress. This effect may not be evident under all conditions, but may become relevant under specific circumstances; for instance, at a given stage during cancer evolution, in response to a certain therapy, or in selected subpopulations of the tumor mass. Currently, there is a lack of experimental studies aimed to test this hypothesis, and we encourage research in this direction. Similarly, it may be important to define the specific stress conditions associated with a given tumor and/or chemotherapeutic drug; a better comprehension of this complexity may help predict the efficacy of treatments, in particular those inducing ferroptosis, in cancers with or without p53 mutation.

Research in the past decades led to development of several drugs that specifically target mutant p53, either by destabilizing the protein to reduce its levels, or by modulating its conformation to restore p53 tumor-suppressive functions (Dolma and Muller, 2022; Hassin and Oren, 2022; Levine, 2022). Such molecules are being tested for clinical use in combination with chemotherapy in p53 mutated cancers, with variable results. Many chemotherapeutic drugs can induce ferroptosis in addition to their primary action (e.g., cisplatin, gemcitabine, sorafenib); in preclinical cancer models their action is increased by co-treatment with ferroptosis inducers, such as drugs that inhibit System Xc⁻, reduce GSH, inhibit GPX4, or alter intracellular iron levels (Su et al., 2020; Wu et al., 2020; Lei et al., 2022). In this scenario, we hypothesize that targeting mutant p53 may increase the efficacy of pro-ferroptotic drugs under specific stress conditions, thus improving the clinical response of p53 mutated tumors.

References

• 1

  AnsariA.RahmanM. S.SahaS. K.SaikotF. K.DeepA.KimK. H. (2017). Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease. Aging Cell16 (1), 4–16. 10.1111/acel.12538

  • CrossRef
  • Google Scholar

• 2

  BaiY.MengL.HanL.JiaY.ZhaoY.GaoH.et al (2019). Lipid storage and lipophagy regulates ferroptosis. Biochem. biophysical Res. Commun.508 (4), 997–1003. 10.1016/J.BBRC.2018.12.039

  • CrossRef
  • Google Scholar

• 3

  BellazzoA.SicariD.ValentinoE.Del SalG.CollavinL. (2018). Complexes formed by mutant p53 and their roles in breast cancer. Breast Cancer (Dove Med. Press)10, 101–112. 10.2147/BCTT.S145826

  • CrossRef
  • Google Scholar

• 4

  BersukerK.HendricksJ. M.LiZ.MagtanongL.FordB.TangP. H.et al (2019). The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature575 (7784), 688–692. 10.1038/s41586-019-1705-2

  • CrossRef
  • Google Scholar

• 5

  BirsenR.LarrueC.DecroocqJ.JohnsonN.GuiraudN.GotanegreM.et al (2021). APR-246 induces early cell death by ferroptosis in acute myeloid leukemia. Haematologica107 (2), 403–416. 10.3324/haematol.2020.259531

  • CrossRef
  • Google Scholar

• 6

  BoudreauH. E.CasterlineB. W.BurkeD. J.LetoT. L. (2014). Wild-type and mutant p53 differentially regulate NADPH oxidase 4 in TGF-β-mediated migration of human lung and breast epithelial cells. Br. J. Cancer110 (10), 2569–2582. 10.1038/bjc.2014.165

  • CrossRef
  • Google Scholar

• 7

  BrozD. K.AttardiL. D. (2013). TRP53 activates a global autophagy program to promote tumor suppression. Autophagy9 (9), 1440–1442. 10.4161/auto.25833

  • CrossRef
  • Google Scholar

• 8

  CapaciV.BascettaL.FantuzM.BeznoussenkoG. V.SommaggioR.CancilaV.et al (2020). Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome. Nat. Commun.11 (1), 3945. 10.1038/s41467-020-17596-5

  • CrossRef
  • Google Scholar

• 9

  ChenD.ChuB.YangX.LiuZ.JinY.KonN.et al (2021). iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4. Nat. Commun.12 (1), 3644. 10.1038/s41467-021-23902-6

  • CrossRef
  • Google Scholar

• 10

  ChenX.Cubillos-RuizJ. R. (2021). Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat. Rev. Cancer21 (2), 71–88. 10.1038/s41568-020-00312-2

  • CrossRef
  • Google Scholar

• 11

  ChenY.FuL. L.WenX.WangX. Y.LiuJ.ChengY.et al (2014). Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer. Cell Death Dis.5 (2), e1047. 10.1038/cddis.2014.14

  • CrossRef
  • Google Scholar

• 12

  CorazzariM.FimiaG. M.LovatP.PiacentiniM. (2013). Why is autophagy important for melanoma? Molecular mechanisms and therapeutic implications. Semin. Cancer Biol.23 (5), 337–343. 10.1016/j.semcancer.2013.07.001

  • CrossRef
  • Google Scholar

• 13

  CorazzariM.GagliardiM.FimiaG. M.PiacentiniM. (2017). Endoplasmic reticulum stress, unfolded protein response, and cancer cell fate. Front. Oncol.7 (APR), 78. 10.3389/fonc.2017.00078

  • CrossRef
  • Google Scholar

• 14

  CordaniM.ButeraG.PacchianaR.DonadelliM. (2017). Molecular interplay between mutant p53 proteins and autophagy in cancer cells. Biochimica biophysica acta1867 (1), 19–28. 10.1016/j.bbcan.2016.11.003

  • CrossRef
  • Google Scholar

• 15

  DixonS. J.LembergK. M.LamprechtM. R.SkoutaR.ZaitsevE. M.GleasonC. E.et al (2012). Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell149 (5), 1060–1072. 10.1016/j.cell.2012.03.042

  • CrossRef
  • Google Scholar

• 16

  DixonS. J.PatelD. N.WelschM.SkoutaR.LeeE. D.HayanoM.et al (2014). Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife3, e02523. 10.7554/eLife.02523

  • CrossRef
  • Google Scholar

• 17

  DollS.FreitasF. P.ShahR.AldrovandiM.da SilvaM. C.IngoldI.et al (2019). FSP1 is a glutathione-independent ferroptosis suppressor. Nature575 (7784), 693–698. 10.1038/s41586-019-1707-0

  • CrossRef
  • Google Scholar

• 18

  DolmaL.MullerP. A. J. (2022). GOF mutant p53 in cancers: A therapeutic challenge. Cancers14 (20), 5091. 10.3390/cancers14205091

  • CrossRef
  • Google Scholar

• 19

  D’OraziG.CironeM. (2019). Mutant p53 and cellular stress pathways: A criminal alliance that promotes cancer progression. Cancers11 (5), 614. 10.3390/cancers11050614

  • CrossRef
  • Google Scholar

• 20

  ErikssonS. E.CederS.BykovV. J. N.WimanK. G. (2019). p53 as a hub in cellular redox regulation and therapeutic target in cancer. J. Mol. Cell Biol.11 (4), 330–341. 10.1093/jmcb/mjz005

  • CrossRef
  • Google Scholar

• 21

  ErlansonD. A.DavisB. J.JahnkeW. (2019). Fragment-based drug discovery: Advancing fragments in the absence of crystal structures. Cell Chem. Biol.26 (1), 9–15. 10.1016/J.CHEMBIOL.2018.10.001

  • CrossRef
  • Google Scholar

• 22

  Friedmann AngeliJ. P.KryskoD. V.ConradM. (2019). Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat. Rev. Cancer19 (7), 405–414. 10.1038/S41568-019-0149-1

  • CrossRef
  • Google Scholar

• 23

  FujiharaK. M.ZhangB. Z.JacksonT. D.OgunkolaM. O.NijagalB.MilneJ. V.et al (2022). Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction. Sci. Adv.8 (37), eabm9427. 10.1126/sciadv.abm9427

  • CrossRef
  • Google Scholar

• 24

  GagliardiM.CotellaD.SantoroC.CoraD.BarlevN. A.PiacentiniM.et al (2019). Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis. Cell Death Dis.10 (12), 902. 10.1038/s41419-019-2143-7

  • CrossRef
  • Google Scholar

• 25

  GagliardiM.SaverioV.MonzaniR.FerrariE.PiacentiniM.CorazzariM. (2020). Ferroptosis: A new unexpected chance to treat metastatic melanoma?Cell cycleGeorget. Tex.)19 (19), 2411–2425. 10.1080/15384101.2020.1806426

  • CrossRef
  • Google Scholar

• 26

  GalluzziL.de SantiM.CrinelliR.de MarcoC.ZaffaroniN.DurantiA.et al (2012). Induction of endoplasmic reticulum stress response by the indole-3-carbinol cyclic tetrameric derivative CTet in human breast cancer cell lines. PLoS ONE7 (8), e43249. 10.1371/JOURNAL.PONE.0043249

  • CrossRef
  • Google Scholar

• 27

  GalluzziL.PietrocolaF.Bravo-San PedroJ. M.AmaravadiR. K.BaehreckeE. H.CecconiF.et al (2015). Autophagy in malignant transformation and cancer progression. EMBO J.34 (7), 856–880. 10.15252/embj.201490784

  • CrossRef
  • Google Scholar

• 28

  GnanapradeepanK.BasuS.BarnoudT.Budina-KolometsA.KungC.-P.MurphyM. E. (2018). The p53 tumor suppressor in the control of metabolism and ferroptosis. Front. Endocrinol.9, 124. 10.3389/fendo.2018.00124

  • CrossRef
  • Google Scholar

• 29

  GreenD. R.KroemerG. (2009). Cytoplasmic functions of the tumour suppressor p53. Nature458 (7242), 1127–1130. 10.1038/nature07986

  • CrossRef
  • Google Scholar

• 30

  HassinO.OrenM. (2022). Drugging p53 in cancer: One protein, many targets. Nat. Rev. Drug Discov.22, 127–144. 10.1038/s41573-022-00571-8

  • CrossRef
  • Google Scholar

• 31

  HongY.RenT.WangX.LiuX.FeiY.MengS.et al (2022). APR-246 triggers ferritinophagy and ferroptosis of diffuse large B-cell lymphoma cells with distinct TP53 mutations. Leukemia36 (9), 2269–2280. 10.1038/s41375-022-01634-w

  • CrossRef
  • Google Scholar

• 32

  HouW.XieY.SongX.SunX.LotzeM. T.ZehH. J.et al (2016). Autophagy promotes ferroptosis by degradation of ferritin. Autophagy12 (8), 1425–1428. 10.1080/15548627.2016.1187366

  • CrossRef
  • Google Scholar

• 33

  JiangL.HickmanJ. H.WangS.-J.GuW. (2015a). Dynamic roles of p53-mediated metabolic activities in ROS-induced stress responses. Cell Cycle14 (18), 2881–2885. 10.1080/15384101.2015.1068479

  • CrossRef
  • Google Scholar

• 34

  JiangL.KonN.LiT.WangS.-J.SuT.HibshooshH.et al (2015b). Ferroptosis as a p53-mediated activity during tumour suppression. Nature520 (7545), 57–62. 10.1038/nature14344

  • CrossRef
  • Google Scholar

• 35

  JiangX.StockwellB. R.ConradM. (2021). Ferroptosis: Mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol.22 (4), 266–282. 10.1038/S41580-020-00324-8

  • CrossRef
  • Google Scholar

• 36

  JinY.GuW.ChenW. (2021). Sirt3 is critical for p53-mediated ferroptosis upon ROS-induced stress. J. Mol. Cell Biol.13 (2), 151–154. 10.1093/jmcb/mjaa074

  • CrossRef
  • Google Scholar

• 37

  KandothC.McLellanM. D.VandinF.YeK.NiuB.LuC.et al (2013). Mutational landscape and significance across 12 major cancer types. Nature502 (7471), 333–339. 10.1038/nature12634

  • CrossRef
  • Google Scholar

• 38

  KennedyM. C.LoweS. W. (2022). Mutant p53: it’s not all one and the same. Cell Death Differ.29 (5), 983–987. 10.1038/s41418-022-00989-y

  • CrossRef
  • Google Scholar

• 39

  KimM. P.LozanoG. (2018). Mutant p53 partners in crime. Cell death Differ.25, 161–168. 10.1038/cdd.2017.185

  • CrossRef
  • Google Scholar

• 40

  KraftV. A. N.BezjianC. T.PfeifferS.RingelstetterL.MüllerC.ZandkarimiF.et al (2020). GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Central Sci.6 (1), 41–53. 10.1021/acscentsci.9b01063

  • CrossRef
  • Google Scholar

• 41

  LeiG.ZhuangL.GanB. (2022). Targeting ferroptosis as a vulnerability in cancer. Nat. Rev. Cancer22 (7), 381–396. 10.1038/S41568-022-00459-0

  • CrossRef
  • Google Scholar

• 42

  LevineA. J. (2020). p53: 800 million years of evolution and 40 years of discovery. Nat. Rev. Cancer20 (8), 471–480. 10.1038/s41568-020-0262-1

  • CrossRef
  • Google Scholar

• 43

  LevineA. J. (2022). Targeting the P53 protein for cancer therapies: The translational impact of P53 research. Cancer Res.82 (3), 362–364. 10.1158/0008-5472.can-21-2709

  • CrossRef
  • Google Scholar

• 44

  LiJ.LamaR.GalsterS. L.InigoJ. R.WuJ.ChandraD.et al (2022). Small molecule MMRi62 induces ferroptosis and inhibits metastasis in pancreatic cancer via degradation of ferritin heavy chain and mutant p53. Mol. Cancer Ther.21 (4), 535–545. 10.1158/1535-7163.mct-21-0728

  • CrossRef
  • Google Scholar

• 45

  LimiaC. M.SauzayC.UrraH.HetzC.ChevetE.AvrilT. (2019). Emerging roles of the endoplasmic reticulum associated unfolded protein response in cancer cell migration and invasion. Cancers (Basel)11 (5), 631. 10.3390/cancers11050631

  • CrossRef
  • Google Scholar

• 46

  LisekK.CampanerE.CianiY.WalerychD.Del SalG. (2018). Mutant p53 tunes the NRF2-dependent antioxidant response to support survival of cancer cells. Oncotarget9 (29), 20508–20523. 10.18632/oncotarget.24974

  • CrossRef
  • Google Scholar

• 47

  LiuD. S.DuongC. P.HauptS.MontgomeryK. G.HouseC. M.AzarW. J.et al (2017). Inhibiting the system xC(-)/glutathione axis selectively targets cancers with mutant-p53 accumulation. Nat. Commun.8, 14844. 10.1038/ncomms14844

  • CrossRef
  • Google Scholar

• 48

  LiuJ.KangR.TangD. (2021a). Signaling pathways and defense mechanisms of ferroptosis. FEBS J.289, 7038–7050. 10.1111/FEBS.16059

  • CrossRef
  • Google Scholar

• 49

  LiuJ.ZhangC.WangJ.HuW.FengZ. (2020). The regulation of ferroptosis by tumor suppressor p53 and its pathway. Int. J. Mol. Sci.21 (21), 8387. 10.3390/ijms21218387

  • CrossRef
  • Google Scholar

• 50

  LiuL.LiL.LiM.LuoZ. (2021b). Autophagy-dependent ferroptosis as a therapeutic target in cancer. ChemMedChem16 (19), 2942–2950. 10.1002/CMDC.202100334

  • CrossRef
  • Google Scholar

• 51

  LiuY.GuW. (2022b). p53 in ferroptosis regulation: the new weapon for the old guardian. Cell Death Differ.29 (5), 895–910. 10.1038/s41418-022-00943-y

  • CrossRef
  • Google Scholar

• 52

  LiuY.GuW. (2022a). The complexity of p53-mediated metabolic regulation in tumor suppression. Seminars Cancer Biol.85, 4–32. 10.1016/j.semcancer.2021.03.010

  • CrossRef
  • Google Scholar

• 53

  MadanE.ParkerT. M.PelhamC. J.PalmaA. M.PeixotoM. L.NaganeM.et al (2019). HIF-transcribed p53 chaperones HIF-1α. Nucleic Acids Res.47 (19), 10212–10234. 10.1093/nar/gkz766

  • CrossRef
  • Google Scholar

• 54

  MagriJ.GasparettoA.ContiL.CalauttiE.CossuC.RuiuR.et al (2021). Tumor-associated antigen xCT and mutant-p53 as molecular targets for new combinatorial antitumor strategies. Cells10 (1), 108. 10.3390/cells10010108

  • CrossRef
  • Google Scholar

• 55

  MaiuriM. C.GalluzziL.MorselliE.KeppO.MalikS. A.KroemerG. (2010). Autophagy regulation by p53. Curr. Opin. Cell Biol.22 (2), 181–185. 10.1016/j.ceb.2009.12.001

  • CrossRef
  • Google Scholar

• 56

  ManciasJ. D.WangX.GygiS. P.HarperJ. W.KimmelmanA. C. (2014). Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature509 (7498), 105–109. 10.1038/NATURE13148

  • CrossRef
  • Google Scholar

• 57

  MantovaniF.CollavinL.Del SalG. (2019). Mutant p53 as a guardian of the cancer cell. Cell Death Differ.26 (2), 199–212. 10.1038/s41418-018-0246-9

  • CrossRef
  • Google Scholar

• 58

  MaoC.LiuX.ZhangY.LeiG.YanY.LeeH.et al (2021). DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature593:(7860), 586–590. 10.1038/s41586-021-03539-7

  • CrossRef
  • Google Scholar

• 59

  MorselliE.TasdemirE.MaiuriM. C.GalluzziL.KeppO.CriolloA.et al (2008). Mutant p53 protein localized in the cytoplasm inhibits autophagy. Cell cycleGeorget. Tex)7 (19), 3056–3061. PMID - 18818522 7. 10.4161/cc.7.19.6751

  • CrossRef
  • Google Scholar

• 60

  MrakovcicM.FröhlichL. F. (2018). p53-Mediated molecular control of autophagy in tumor cells. Biomolecules8 (2), 14. 10.3390/biom8020014

  • CrossRef
  • Google Scholar

• 61

  PagliariniV.GiglioP.BernardoniP.De ZioD.FimiaG. M.PiacentiniM.et al (2015). Downregulation of E2F1 during ER stress is required to induce apoptosis. J. Cell Sci.128 (6), 1166–1179. 10.1242/jcs.164103

  • CrossRef
  • Google Scholar

• 62

  PilleyS.RodriguezT. A.VousdenK. H. (2021). Mutant p53 in cell-cell interactions. Genes and Dev.35 (7-8), 433–448. 10.1101/gad.347542.120

  • CrossRef
  • Google Scholar

• 63

  PizzinoG.IrreraN.CucinottaM.PallioG.ManninoF.ArcoraciV.et al (2017). Oxidative stress: Harms and benefits for human Health. Oxidative Med. Cell. Longev.2017, 8416763. 10.1155/2017/8416763

  • CrossRef
  • Google Scholar

• 64

  RodriguezR.SchreiberS. L.ConradM. (2022). Persister cancer cells: Iron addiction and vulnerability to ferroptosis. Mol. Cell82 (4), 728–740. 10.1016/J.MOLCEL.2021.12.001

  • CrossRef
  • Google Scholar

• 65

  Rojo de la VegaM.ChapmanE.ZhangD. D. (2018). NRF2 and the hallmarks of cancer. Cancer Cell34 (1), 21–43. 10.1016/j.ccell.2018.03.022

  • CrossRef
  • Google Scholar

• 66

  SeilerA.SchneiderM.FörsterH.RothS.WirthE. K.CulmseeC.et al (2008). Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab.8 (3), 237–248. 10.1016/J.CMET.2008.07.005

  • CrossRef
  • Google Scholar

• 67

  SenftD.RonaiZ. E. (2016). Adaptive stress responses during tumor metastasis and dormancy. Trends Cancer2 (8), 429–442. 10.1016/j.trecan.2016.06.004

  • CrossRef
  • Google Scholar

• 68

  SermeusA.MichielsC. (2011). Reciprocal influence of the p53 and the hypoxic pathways. Cell Death Dis.2 (5), e164. 10.1038/cddis.2011.48

  • CrossRef
  • Google Scholar

• 69

  ShahR.ShchepinovM. S.PrattD. A. (2018). Resolving the role of lipoxygenases in the initiation and execution of ferroptosis. ACS Central Sci.4 (3), 387–396. 10.1021/acscentsci.7b00589

  • CrossRef
  • Google Scholar

• 70

  ShiY.NorbergE.Vakifahmetoglu-NorbergH. (2021). Mutant p53 as a regulator and target of autophagy. Front. Oncol.10, 607149. 10.3389/fonc.2020.607149

  • CrossRef
  • Google Scholar

• 71

  SicariD.FantuzM.BellazzoA.ValentinoE.ApollonioM.PontissoI.et al (2019). Mutant p53 improves cancer cells’ resistance to endoplasmic reticulum stress by sustaining activation of the UPR regulator ATF6. Oncogene38 (34), 6184–6195. 10.1038/s41388-019-0878-3

  • CrossRef
  • Google Scholar

• 72

  StockwellB. R. (2022). Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell185 (14), 2401–2421. 10.1016/J.CELL.2022.06.003

  • CrossRef
  • Google Scholar

• 73

  SuX.XieY.ZhangJ.LiM.ZhangQ.JinG.et al (2022). HIF-α activation by the prolyl hydroxylase inhibitor roxadustat suppresses chemoresistant glioblastoma growth by inducing ferroptosis. Cell death Dis.13 (10), 861. 10.1038/S41419-022-05304-8

  • CrossRef
  • Google Scholar

• 74

  SuY.ZhaoB.ZhouL.ZhangZ.ShenY.LvH.et al (2020). Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs. Cancer Lett.483, 127–136. 10.1016/j.canlet.2020.02.015

  • CrossRef
  • Google Scholar

• 75

  Szewczyk-GolecK.CzuczejkoJ.TylzanowskiP.LeckaJ. (2018). Strategies for modulating oxidative stress under diverse physiological and pathological conditions. Oxidative Med. Cell. Longev.2018, 3987941. 10.1155/2018/3987941

  • CrossRef
  • Google Scholar

• 76

  VogiatziF.BrandtD. T.SchneikertJ.FuchsJ.GrikscheitK.WanzelM.et al (2016). Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5. Proc. Natl. Acad. Sci.113 (52), E8433–E8442. 10.1073/pnas.1612711114

  • CrossRef
  • Google Scholar

• 77

  WalerychD.LisekK.SommaggioR.PiazzaS.CianiY.DallaE.et al (2016). Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer. Nat. Cell Biol.18 (8), 897–909. 10.1038/ncb3380

  • CrossRef
  • Google Scholar

• 78

  WangH.JiangH.Van De GuchtM.De RidderM. (2019). Hypoxic radioresistance: Can ROS Be the key to overcome it?Cancers11 (1), 112. 10.3390/CANCERS11010112

  • CrossRef
  • Google Scholar

• 79

  WangS. J.LiD.OuY.JiangL.ChenY.ZhaoY.et al (2016). Acetylation is crucial for p53-mediated ferroptosis and tumor suppression. Cell Rep.17 (2), 366–373. 10.1016/j.celrep.2016.09.022

  • CrossRef
  • Google Scholar

• 80

  WangZ.StrasserA.KellyG. L. (2022). Should mutant TP53 be targeted for cancer therapy?Cell Death Differ.29 (5), 911–920. 10.1038/s41418-022-00962-9

  • CrossRef
  • Google Scholar

• 81

  WuY.YuC.LuoM.CenC.QiuJ.ZhangS.et al (2020). Ferroptosis in cancer treatment: Another way to rome. Front. Oncol.10, 571127. 10.3389/fonc.2020.571127

  • CrossRef
  • Google Scholar

• 82

  WuZ.GengY.LuX.ShiY.WuG.ZhangM.et al (2019). Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc. Natl. Acad. Sci. U. S. A.116 (8), 2996–3005. 10.1073/PNAS.1819728116

  • CrossRef
  • Google Scholar

• 83

  YangG.ShiR.ZhangQ. (2020). Hypoxia and oxygen-sensing signaling in gene regulation and cancer progression. Int. J. Mol. Sci.21 (21), 8162–8224. 10.3390/IJMS21218162

  • CrossRef
  • Google Scholar

• 84

  YangM.ChenP.LiuJ.ZhuS.KroemerG.KlionskyD. J.et al (2019). Clockophagy is a novel selective autophagy process favoring ferroptosis. Sci. Adv.5 (7), eaaw2238. 10.1126/SCIADV.AAW2238

  • CrossRef
  • Google Scholar

• 85

  YangW. S.StockwellB. R. (2016). Ferroptosis: Death by lipid peroxidation. Trends Cell Biol.26 (3), 165–176. 10.1016/j.tcb.2015.10.014

  • CrossRef
  • Google Scholar

• 86

  ZhouB.LiuJ.KangR.KlionskyD. J.KroemerG.TangD. (2020). Ferroptosis is a type of autophagy-dependent cell death. Seminars cancer Biol.66, 89–100. 10.1016/J.SEMCANCER.2019.03.002

  • CrossRef
  • Google Scholar

• 87

  ZhouG.WangJ.ZhaoM.XieT.-X.TanakaN.SanoD.et al (2014). Gain-of-Function mutant p53 promotes cell growth and cancer cell metabolism via inhibition of AMPK activation. Mol. Cell54, 960–974. 10.1016/j.molcel.2014.04.024

  • CrossRef
  • Google Scholar

• 88

  ZouY.LiH.GrahamE. T.DeikA. A.EatonJ. K.WangW.et al (2020). Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat. Chem. Biol.16, (3), 302–309. 10.1038/s41589-020-0472-6

  • CrossRef
  • Google Scholar