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Review Article

The Relationship between Ferroptosis and Tumors: A Novel Landscape for Therapeutic Approach

Author(s): Xiaojun Xia, Xiaoping Fan*, Mingyi Zhao* and Ping Zhu*

Volume 19, Issue 2, 2019

Page: [117 - 124] Pages: 8

DOI: 10.2174/1566523219666190628152137

open access plus

Abstract

Background: Ferroptosis is a newly discovered form of iron-dependent oxidative cell death characterized by lethal accumulation of lipid-based reactive oxygen species (ROS). It is distinct from other forms of cell death including apoptosis, necrosis, and autophagy in terms of morphology, biochemistry and genetics.

Discussion: Ferroptosis can be induced by system xc- inhibitors or glutathione peroxidase 4 (GPx4) inhibitors, as well as drugs such as sorafenib, sulfasalazine (SAS), and artesunate (ART). Ferroptosis has been recently shown to be critical in regulating growth of tumors, such as hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic carcinoma, and diffuse large B cell lymphoma (DLBCL). Ferroptosis is also associated with resistance to chemotherapeutic drugs and the anti-tumor efficacy of immunotherapy.

Conclusion: This review summarizes the mechanism of ferroptosis and its relationship with different types of tumors, to advance our understanding of cell death and to find a novel approach for clinical cancer management.

Keywords: Ferroptosis, iron metabolism, ROS, cancer, chemotherapeutic drug resistance therapeutic approach.

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Graphical Abstract

[1]
Gao M, Monian P, Jiang X, et al. Metabolism and iron signaling in ferroptotic cell death. Oncotarget 2015; 6(34): 35145-6.
[2]
Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149(5): 1060-72.
[3]
Cao JY, Dixon SJ. Mechanisms of ferroptosis. Cell Mol Life Sci 2016; 73(11-12): 2195-209.
[4]
Dolma S, Lessnick SL, Hahn WC, et al. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 2003; 3(3): 285-96.
[5]
Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol 2008; 15(3): 234-45.
[6]
Toyokuni S, Ito F, Yamashita K, et al. Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis. Free Radic Biol Med 2017; 108: 610-26.
[7]
Cramer SL, Saha A, Liu J, Tadi S, et al. Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth. Nat Med 2017; 23(1): 120-7.
[8]
Yang WS. SriRamaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014; 156(1-2): 317-31.
[9]
Kim SE, Zhang L, Ma K, et al. Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nat Nanotechnol 2016; 11(11): 977-85.
[10]
Yang WS. SriRamaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014; 156(1-2): 317-31.
[11]
Sato H, Tamba M, Ishii T, et al. Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J Biol Chem 1999; 274(17): 11455-8.
[12]
Conrad M, Sato H. The oxidative stress-inducible cystine/glutamate antiporter, system x (c) (-): cystine supplier and beyond. Amino Acids 2012; 42(1): 231-46.
[13]
Lewerenz J, Hewett SJ, Huang Y, et al. The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities. Antioxid Redox Signal 2013; 18(5): 522-55.
[14]
Ishii T, Bannai S, Sugita Y, et al. Mechanism of growth stimulation of L1210 cells by 2-mercaptoethanol in vitro. Role of the mixed disulfide of 2-mercaptoethanol and cysteine. J Biol Chem 1981; 256(23): 12387-92.
[15]
Dixon SJ, Patel DN, Welsch M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife 2014; 3e2523
[16]
Torti SV, Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer 2013; 13(5): 342-55.
[17]
Manz DH, Blanchette NL, Paul BT, et al. Iron and cancer: recent insights. Ann N Y Acad Sci 2016; 1368(1): 149-61.
[18]
Yagoda N, von Rechenberg M, Zaganjor E, et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 2007; 447(7146): 864-8.
[19]
Dixon SJ, Patel DN, Welsch M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife 2014; 3e2523
[20]
Sun X, Ou Z, Xie M, et al. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene 2015; 34(45): 5617-25.
[21]
Tan S, Schubert D, Maher P, et al. Oxytosis: A novel form of programmed cell death. Curr Top Med Chem 2001; 1(6): 497-506.
[22]
Bridges RJ, Natale NR, Patel SA, et al. System xc (-) cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol 2012; 165(1): 20-34.
[23]
Mehta A, Prabhakar M, Kumar P, et al. Excitotoxicity: bridge to various triggers in neurodegenerative disorders. Eur J Pharmacol 2013; 698(1-3): 6-18.
[24]
Wolpaw AJ, Shimada K, Skouta R, et al. Modulatory profiling identifies mechanisms of small molecule-induced cell death. Proc Natl Acad Sci USA 2011; 108(39): E771-80.
[25]
Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol 2008; 15(3): 234-45.
[26]
Brigelius-Flohe R, Maiorino M. Glutathione peroxidases. Biochim Biophys Acta 2013; 1830(5): 3289-303.
[27]
Friedmann Angeli JP, Schneider M, Proneth B, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 2014; 16: 1180-91.
[28]
Imai H, Nakagawa Y. Biological significance of phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) in mammalian cells. Free Radic Biol Med 2003; 34: 145-69.
[29]
Xie Y, Song X, Sun X, et al. Identification of baicalein as a ferroptosis inhi- bitor by natural product library screening. Biochem Biophys Res Commun 2016; 473: 775-80.
[30]
Shintoku R, Takigawa Y, Yamada K, et al. Lipoxygenase-mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3. Cancer Sci 2017; 108: 2187-94.
[31]
Jiang L, Kon N, Li T, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 2015; 520(7545): 57-62.
[32]
Liu DS, Duong CP, Haupt S, et al. Inhibiting the system xC (-)/glutathione axis selectively targets cancers with mutant-p53 accumulation. Nat Commun 2017; 8: 14844.
[33]
Wang SJ, Li DW, Ou Y, et al. Acetylation is crucial for p53-mediated Ferroptosis and Tumor Suppression. Cell Rep 2016; 17(2): 366-73.
[34]
Gao M, Monian P, Quadri N, et al. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell 2015; 59: 298-308.
[35]
Chao Mao, Xiang Wang, Yating Liu, et al. A G3BP1-interacting lncRNA promotes ferroptosis and apoptosis in cancer via nuclear sequestration of p53. Cancer Res 2018; 78(13): 3484-96.
[36]
Min Wang, Chao Mao, Lianlian Ouyang, et al. Long. noncoding RNA LINC00336 inhibits ferroptosis in lung cancer by functioning as a competing endogenous RNA. Cell Death Differ 2019.
[http://dx.doi.org/10.1038/s41418-019-0304-y]
[37]
Zhang K, Wu L, Zhang P, et al. miR-9 regulates ferroptosis by targeting glutamic-oxaloacetic transaminase GOT1 in melanoma. Mol Carcinog 2018; 57: 1566-7.
[38]
Wu Y, Sun X, Song B, et al. MiR-375/SLC7A11 axis regulates oral squamous cell carcinoma proliferation and invasion. Cancer Med 2017; 6: 1686-97.
[39]
Drayton RM, Dudziec E, Peter S, et al. Reduced expression of miRNA-27a modulates cisplatin resistance in bladder cancer by targeting the cystine/glutamate exchanger SLC7A11. Clin Cancer Res 2014; 20: 1990-2000.
[40]
Liu XX, Li XJ, Zhang B, et al. MicroRNA-26b is underexpressed in human breast cancer and induces cell apoptosis by targeting SLC7A11. FEBS Lett 2011; 585: 1363-7.
[41]
Kabaria S, Choi DC, Chaudhuri AD, et al. MicroRNA-7 activates Nrf2 pathway by targeting Keap1 expression. Free Radic Biol Med 2015; 89: 548-56.
[42]
Babu KR, Muckenthaler MU. miR-20a regulates expression of the iron exporter ferroportin in lung cancer. J Mol Med (Berl) 2016; 94: 347-59.
[43]
Yoshioka Y, Kosaka N, Ochiya T, et al. Micromanaging iron homeostasis: hypoxia-inducible micro-RNA-210 suppresses iron homeostasis-related proteins. J Biol Chem 2012; 287: 34110-9.
[44]
Kindrat I, Tryndyak V, de Conti A, et al. MicroRNA-152-mediated dysregulation of hepatic transferrin receptor 1 in liver carcinogenesis. Oncotarget 2016; 7: 1276-87.
[45]
Shpyleva SI, Tryndyak VP, Kovalchuk O, et al. Role of ferritin alterations in human breast cancer cells. Breast Cancer Res Treat 2011; 126: 63-71.
[46]
Andolfo I, De Falco L, Asci R, et al. Regulation of divalent metal transporter 1 (DMT1) non-IRE isoform by the microRNA let-7d in erythroid cells. Haematologica 2010; 95: 1244-52.
[47]
Wu X, Zhi F, Lun W, et al. Baicalin inhibits PDGF-BB-induced hepatic stellate cell proliferation, apoptosis, invasion, migration and activation via the miR-3595/ACSL4 axis. Int J Mol Med 2018; 41: 1992-2002.
[48]
Zhang Y, Zheng S, Geng Y, et al. MicroRNA profiling of atrial fibrillation in canines: miR-206 modulates intrinsic cardiac autonomic nerve remodeling by regulating SOD1. PLoS One 2015; 10e0122674
[49]
Kyrychenko S, Kyrychenko V, Badr MA, et al. Pivotal role of miR-448 in the development of ROS-induced cardiomyopathy. Cardiovasc Res 2015; 108: 324-34.
[50]
Hass C, Belz K, Schoeneberger H, et al. Sensitization of acute lymphoblastic leukemia cells for LCL161-induced cell death by targeting redox homeostasis. Biochem Pharmacol 2016; 105: 14-22.
[51]
Yu Y, Xie Y, Cao L, et al. The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents. Mol Cell Oncol 2015; 2(4)e1054549
[52]
Hao S, Yu J, He W, et al. Cysteine Dioxygenase 1 Mediates Erastin-Induced Ferroptosis in Human Gastric Cancer Cells. Neoplasia 2017; 19(12): 1022-32.
[53]
Wang SF, Chen MS, Chou YC, et al. Mitochondrial dysfunction enhances cisplatin resistance in human gastric cancer cells via the ROS-activated GCN2-eIF2alpha-ATF4-xCT pathway. Oncotarget 2016; 7(45): 74132-51.
[54]
Ohman KA, Hashim YM, Vangveravong S, et al. Conjugation to the sigma-2 ligand SV119 overcomes uptake blockade and converts dm-Erastin into a potent pancreatic cancer therapeutic. Oncotarget 2016; 7(23): 33529-41.
[55]
Yamaguchi H, Hsu JL, Chen CT, et al. Caspase-independent cell death is involved in the negative effect of EGF receptor inhibitors on cisplatin in non-small cell lung cancer cells. Clin Cancer Res 2013; 19(4): 845-54.
[56]
Roh JL, Kim EH, Jang HJ, et al. Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer. Cancer Lett 2016; 381(1): 96-103.
[57]
Chen L, Li X, Liu L, et al. Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-gamma-lyase function. Oncol Rep 2015; 33(3): 1465-74.
[58]
Schott C, Graab U, Cuvelier N, et al. Oncogenic RAS Mutants Confer Resistance of RMS13 Rhabdomyosarcoma Cells to Oxidative Stress-Induced Ferroptotic Cell Death. Front Oncol 2015; 5: 131.
[59]
Louandre C, Ezzoukhry Z, Godin C, et al. Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib. Int J Cancer 2013; 133(7): 1732-42.
[60]
Lachaier E, Louandre C, Godin C, et al. Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors. Anticancer Res 2014; 34(11): 6417-22.
[61]
Houessinon A, Francois C, Sauzay C, et al. Metallothionein-1 as a biomarker of altered redox metabolism in hepatocellular carcinoma cells exposed to sorafenib. Mol Cancer 2016; 15(1): 38.
[62]
Sun X, Niu X, Chen R, et al. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology 2016; 64(2): 488-500.
[63]
Sun X, Ou Z, Chen R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology 2016; 63(1): 173-84.
[64]
Bai T, Wang S, Zhao Y, et al. Haloperidol, a sigma receptor 1 antagonist, promotes ferroptosis in hepatocellular carcinoma cells. Biochem Biophys Res Commun 2017; 491(4): 919-25.
[65]
Louandre C, Marcq I, Bouhlal H, et al. The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells. Cancer Lett 2015; 356(2 Pt B): 971-7.
[66]
Gout PW, Simms CR, Robertson MC, et al. In vitro studies on the lymphoma growth-inhibitory activity of sulfasalazine. Anticancer Drugs 2003; 14(1): 21-9.
[67]
Gout PW, Buckley AR, Simms CR, et al. Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)- cystine transporter: a new action for an old drug. Leukemia 2001; 15(10): 1633-40.
[68]
Ooko E, Saeed ME, Kadioglu O, et al. Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells. Phytomedicine 2015; 22(11): 1045-54.
[69]
Greenshields AL, Shepherd TG, Hoskin DW, et al. Contribution of reactive oxygen species to ovarian cancer cell growth arrest and killing by the anti-malarial drug artesunate. Mol Carcinog 2017; 56(1): 75-93.
[70]
Eling N, Reuter L, Hazin J, et al. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience 2015; 2(5): 517-32.
[71]
Zheng DW, Lei Q, Zhu JY, et al. Switching Apoptosis to Ferroptosis: Metal-Organic Network for High-Efficiency Anticancer Therapy. Nano Lett 2017; 17(1): 284-91.
[72]
Ma S, Dielschneider RF, Henson ES, et al. Ferroptosis and autophagy induced cell death occur independently after siramesine and lapatinib treatment in breast cancer cells. PLoS One 2017; 12e0182921
[73]
Buccarelli M, Marconi M, Pacioni S, et al. Inhibition of autophagy increases susceptibility of glioblastoma stem cells to temozolomide by igniting ferroptosis. Cell Death Dis 2018; 9: 841.
[74]
Shen Z, Song J, Yung BC, et al. Emerging strategies of cancer therapy based on ferroptosis. Adv Mater 2018; 30e1704007
[75]
Shaw AT, Winslow MM, Magendantz M, et al. Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. Proc Natl Acad Sci USA 2011; 108: 8773-8.
[76]
Wang W, Green M, Choi JE, et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 2019; 569(7755): 270-4.

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