Ferroptosis as a New Type of Cell Death and its Role in Cancer Treatment
Authors:
Skoupilová Hana; Michalová Eva; Hrstka Roman
Authors‘ workplace:
Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno
Published in:
Klin Onkol 2018; 31(Supplementum 2): 21-26
Category:
Review
doi:
https://doi.org/10.14735/amko20182S21
Overview
Background:
Ferroptosis is a recently discovered type of cell death. It is genetically, morphologically, and biochemically distinct from other types of programmed cell death, such as necrosis, apoptosis, and autophagy. The level of intracellular free iron and reactive oxygen species formation are important for ferroptosis activation, which can occur through either of two key inhibitory processes. The first one involves inhibition of cystine transfer into cells by the cystine/glutamate antiporter system (Xc–). Cystine serves as a precursor for the synthesis of glutathione, a major cellular antioxidant. The second one involves the inhibition of glutathione peroxidase 4, which protects cells from lipid peroxidation. Ferroptosis is associated with many metabolic disorders, including neurological diseases and cancer. Molecules involved in the activation of ferroptotic pathways are involved in protecting cells against stress conditions, and in the maintenance of nicotinamide adenine dinucleotide phosphate and glutathione levels, as well as iron homeostasis. Also important is the connection with autophagy, so called ferritinophagy, in which iron is released from lysosomes into the cytosol. Cascade reactions of free unstable iron atoms with other molecules result in the production of reactive oxygen species that initiate the cellular stress that triggers ferroptosis. In diseases such as cancer where cell death inducing mechanisms, including apoptosis, are usually suppressed by genetic changes, the induction of alternative pathways leading to cell death could provide an attractive treatment strategy.
Conclusion:
In recent years, research into new antimetastatic drugs has focused on the activation of alternative cell death pathways that might overcome disturbed metabolic processes inside cancer cells or the chemotherapy resistance acquired in the course of routine treatment. A number of molecules have been found to induce ferroptosis in tumor cells, suggesting that they may offer new alternatives for anticancer treatment.
Key words:
cell death – cancer – autophagy – ferroptosis – ferritinophagy – cellular stress – ROS
This work was supported by the projects GAČR 17-05838S, MEYS – NPS I – LO1413 and MH CZ- -DRO (MMCI, 00209805).
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
Accepted: 31. 8. 2018
Sources
1. Akera T, Brody TM, Wiest SA. Saturable adenosine 5‘-triphosphate-independent binding of [3H]-ouabain to brain and cardiac tissue in vitro. Br J Pharmacol 1979; 65 (3): 403–409.
2. Gunawardena AH. Programmed cell death and tissue remodelling in plants. J Exp Bot 2008; 59 (3): 445–451. doi: 10.1093/jxb/erm189.
3. Gaussand GM, Jia Q, van der Graaff E et al. Programmed cell death in the leaves of the arabidopsis spontaneous necrotic spots (sns-D) mutant correlates with increased expression of the eukaryotic translation initiation factor eIF4B2. Front Plant Sci 2011; 2: 9. doi: 10.3389/fpls.2011.00009.
4. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell 2004; 116 (2): 205–219.
5. Alberts B, Johnson A, Lewis J et al. Programmed cell death (apoptosis), in molecular biology of the cell. 4th edition. New York: Garland Science 2002.
6. Galluzzi L, Vitale I, Abrams JM et al. Molecular definitions of cell death subroutines: recommendations of the nomenclature committee on cell death 2012. Cell Death Differ 2012; 19 (1): 107–120. doi: 10.1038/cdd.2011.96.
7. Wood W, Turmaine M, Weber R et al. Mesenchymal cells engulf and clear apoptotic footplate cells in macrophageless PU.1 null mouse embryos. Development 2000; 127 (24): 5245–5252.
8. Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature 2001; 411 (6835): 342–348. doi: 10.1038/35077213.
9. Rock KL, Kono H. The inflammatory response to cell death. Annu Rev Pathol 2008; 3: 99–126. doi: 10.1146/annurev.pathmechdis.3.121806.151456.
10. Cotter TG. Apoptosis and cancer: the genesis of a research field. Nat Rev Cancer 2009; 9 (7): 501–507. doi: 10.1038/nrc2663.
11. Ranger AM, Malynn BA, Korsmeyer SJ. Mouse models of cell death. Nat Genet 2001; 28 (2): 113–118. doi: 10.1038/88815.
12. Tait SW, Ichim G, Green DR. Die another way-nonapoptotic mechanisms of cell death. J Cell Sci 2014; 127 (Pt 10): 2135–2144. doi: 10.1242/jcs.093575.
13. McKenzie BA, Mamik MK, Saito LB et al. Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis. Proc Natl Acad Sci U S A 2018; 115 (26): E6065–E6074. doi: 10.1073/pnas.1722041115.
14. Dixon SJ, Lemberg KM, Lamprecht MR et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149 (5): 1060–1072. doi: 10.1016/j.cell.2012.03.042.
15. Vanden Berghe T, Linkermann A, Jouan-Lanhouet S et al. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol 2014; 15 (2): 135–147. doi: 10.1038/nrm3737.
16. Kang R, Tang D. Autophagy andferroptosis – what‘s the connection? Curr Pathobiol Rep 2017; 5 (2): 153–159. doi: 10.1007/s40139-017-0139-5.
17. 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): 234–245. doi: 10.1016/j.chembiol.2008.02.010.
18. 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): 285–296.
19. Vigil D, Cherfils J, Rossman KL et al. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer 2010; 10 (12): 842–857. doi: 10.1038/nrc2960.
20. Mitsuuchi Y, Testa JR. Cytogenetics and molecular genetics of lung cancer. Am J Med Genet 2002; 115 (3): 183–188. doi: 10.1002/ajmg.10692.
21. Ofir Dovrat T, Sokol E, Frampton G et al. Unusually long-term responses to vemurafenib in BRAF V600E mutated colon and thyroid cancers followed by the development of rare RAS activating mutations. Cancer Biol Ther 2018: 1–4. doi: 10.1080/15384047.2018.1480289.
22. Sekita-Hatakeyama Y, Nishikawa T, Takeuchi M et al. K-ras mutation analysis of residual liquid-based cytology specimens from endoscopic ultrasound-guided fine needle aspiration improves cell block diagnosis of pancreatic ductal adenocarcinoma. PLoS One 2018; 13 (3): e0193692. doi: 10.1371/journal.pone.0193692.
23. Garcia-Rostan G, Zhao H, Camp RL et al. ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer. J Clin Oncol 2003; 21 (17): 3226–3235. doi: 10.1200/JCO.2003.10.130.
24. 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): 864–868. doi: 10.1038/nature05859.
25. Cheng Y, Zak O, Aisen P et al. Structure of the human transferrin receptor-transferrin complex. Cell 2004; 116 (4): 565–576.
26. Chan RY, Ponka P, Schulman HM. Transferrin-receptor-independent but iron-dependent proliferation of variant Chinese hamster ovary cells. Exp Cell Res 1992; 202 (2): 326–336.
27. Harrison PM, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta 1996; 1275 (3): 161–203.
28. Terman A, Kurz T. Lysosomal iron, iron chelation, and cell death. Antioxid Redox Signal 2013; 18 (8): 888–898. doi: 10.1089/ars.2012.4885.
29. Guo G, Cui Y. New perspective on targeting the tumor suppressor p53 pathway in the tumor microenvironment to enhance the efficacy of immunotherapy. J Immunother Cancer 2015; 3: 9. doi: 10.1186/s40425-015-0053-5.
30. Wang SJ, Li D, Ou Y et al. Acetylation is crucial for p53-mediated Ferroptosis and tumor suppression. Cell Rep 2016; 17 (2): 366–373. doi: 10.1016/j.celrep.2016.09.022.
31. Winterbourn CC. Toxicity of iron and hydrogen peroxide: the Fenton reaction. Toxicol Lett 1995; 82–83: 969–974.
32. Aisen P, Enns C, Wessling-Resnick M. Chemistry and biology of eukaryotic iron metabolism. Int J Biochem Cell Biol 2001; 33 (10): 940–959.
33. Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell 2004; 117 (3): 285–297.
34. Mancias JD, Wang X, Gygi SP et al. Quantitative proteomics identifies NCOA4 as the cargo receptor media-ting ferritinophagy. Nature 2014; 509 (7498): 105–109. doi: 10.1038/nature13148.
35. Asano T, Komatsu M, Yamaguchi-Iwai Y et al. Distinct mechanisms of ferritin delivery to lysosomes in iron-depleted and iron-replete cells. Mol Cell Biol 2011; 31 (10): 2040–2052. doi: 10.1128/MCB.01437-10.
36. Gunshin H, Mackenzie B, Berger UV et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997; 388 (6641): 482–488. doi: 10.1038/41343.
37. Qian ZM, Li H, Sun H et al. Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacol Rev 2002; 54 (4): 561–587.
38. Donovan A, Lima CA, Pinkus JL et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 2005; 1 (3): 191–200. doi: 10.1016/j.cmet.2005.01.003.
39. Zohn IE, De Domenico I, Pollock A et al. The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease. Blood 2007; 109 (10): 4174–4180. doi: 10.1182/blood-2007-01-066 068.
40. Zhang Z, Zhang F, An P et al. Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. Blood 2011; 118 (7): 1912–1922. doi: 10.1182/blood-2011-01-330324.
41. Dixon SJ, Patel DN, Welsch M et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 2014; 3e02523. doi: 10.7554/eLife.02523.
42. Yang WS, SriRamaratnam R, Welsch ME et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014; 156 (1–2): 317–331. doi: 10.1016/j.cell.2013.12.010.
43. Bannai S, Kitamura E. Transport interaction of L-cystine and L-glutamate in human diploid fibroblasts in culture. J Biol Chem 1980; 255 (6): 2372–2376.
44. Makowske M, Christensen HN. Contrasts in transport systems for anionic amino acids in hepatocytes and a hepatoma cell line HTC. J Biol Chem 1982; 257 (10): 5663–5670.
45. Patel SA, Warren BA, Rhoderick JF et al. Differentiation of substrate and non-substrate inhibitors of transport system xc (-): an obligate exchanger of L-glutamate and L-cystine. Neuropharmacology 2004; 46 (2): 273–284.
46. Bannai S. Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J Biol Chem 1986; 261 (5): 2256-2263.
47. Bannai S. Induction of cystine and glutamate transport activity in human fibroblasts by diethyl maleate and other electrophilic agents. J Biol Chem 1984; 259 (4): 2435–2440.
48. Sato H, Fujiwara K, Sagara J et al. Induction of cystine transport activity in mouse peritoneal macrophages by bacterial lipopolysaccharide. Biochem J 1995; 310 (Pt 2): 547–551.
49. Sakakura Y, Sato H, Shiiya A et al. Expression and function of cystine/glutamate transporter in neutrophils. J Leukoc Biol 2007; 81 (4): 974–982. doi: 10.1189/jlb.0606385.
50. Watanabe H, Bannai S. Induction of cystine transport activity in mouse peritoneal macrophages. J Exp Med 1987; 165 (3): 628–640.
51. Jiang L, Kon N, Li T et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 2015; 520 (7545): 57–62. doi: 10.1038/nature14344.
52. 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 (9): 1363–1367. doi: 10.1016/j.febslet.2011.04.018.
53. Robert SM, Buckingham SC, Campbell SL et al. SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci Transl Med 2015; 7 (289): 289ra286. doi: 10.1126/scitranslmed.aaa8103.
54. Linkermann A, Skouta R, Himmerkus N et al. Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci U S A 2014; 111 (47): 16836–16841. doi: 10.1073/pnas.1415518111.
55. Weiwer M, Bittker JA, Lewis TA et al. Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorg Med Chem Lett 2012; 22 (4): 1822–1826. doi: 10.1016/j.bmcl.2011.09.047.
56. Cao JY, Dixon SJ. Mechanisms of ferroptosis. Cell Mol Life Sci 2016; 73 (11–12): 2195–2209. doi: 10.1007/s00018-016-2194-1.
57. 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): 1633–1640.
58. 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): 517–532. doi: 10.18632/oncoscience.160.
59. 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): 6417–6422.
60. 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): 1732–1742. doi: 10.1002/ijc.28159.
61. Viswanathan VS, Ryan MJ, Dhruv HD et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 2017; 547 (7664): 453–457. doi: 10.1038/nature23007.
62. Brigelius-Flohe R, Maiorino M. Glutathione peroxidases. Biochim Biophys Acta 2013; 1830 (5): 3289–3303. doi: 10.1016/j.bbagen.2012.11.020.
63. Conrad M, Friedmann Angeli JP. Glutathione peroxidase 4 (Gpx4) and ferroptosis: what‘s so special about it? Mol Cell Oncol 2015; 2 (3): e995047. doi: 10.4161/23723556.2014.995047.
64. Takebe G, Yarimizu J, Saito Y et al. A comparative study on the hydroperoxide and thiol specificity of the glutathione peroxidase family and selenoprotein P. J Biol Chem 2002; 277 (43): 41254–41258. doi: 10.1074/jbc.M202773200.
65. Thomas JP, Geiger PG, Maiorino M et al. Enzymatic reduction of phospholipid and cholesterol hydroperoxides in artificial bilayers and lipoproteins. Biochim Biophys Acta 1990; 1045 (3): 252–260.
66. 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 (12): 1180–1191. doi: 10.1038/ncb3064.
67. Skouta R, Dixon SJ, Wang J et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc 2014; 136 (12): 4551–4556. doi: 10.1021/ja411006a.
68. Magtanong L, Ko PJ, Dixon SJ. Emerging roles for lipids in non-apoptotic cell death. Cell Death Differ 2016; 23 (7): 1099–1109. doi: 10.1038/cdd.2016.25.
69. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132 (1): 27–42. doi: 10.1016/j.cell.2007.12.018.
70. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell 2011; 147 (4): 728–741. doi: 10.1016/j.cell.2011.10.026.
71. Gao M, Monian P, Pan Q et al. Ferroptosis is an autophagic cell death process. Cell Res 2016; 26 (9): 1021–1032. doi: 10.1038/cr.2016.95.
72. Hou W, Xie Y, Song X et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 2016; 12 (8): 1425–1428. doi: 10.1080/15548627.2016.1187366.
73. Torii S, Shintoku R, Kubota C et al. An essential role for functional lysosomes in ferroptosis of cancer cells. Biochem J 2016; 473 (6): 769–777. doi: 10.1042/BJ20150658.
74. Cross CE, Halliwell B, Borish ET et al. Oxygen radicals and human disease. Ann Intern Med 1987; 107 (4): 526–545.
75. Chio IIC, Tuveson DA. ROS in Cancer: The Burning Question. Trends Mol Med 2017; 23 (5): 411–429. doi: 10.1016/j.molmed.2017.03.004.
76. Kakhlon O, Gruenbaum Y, Cabantchik ZI. Ferritin expression modulates cell cycle dynamics and cell responsiveness to H-ras-induced growth via expansion of the labile iron pool. Biochem J 2002; 363 (Pt 3): 431–436.
77. Kakhlon O, Gruenbaum Y, Cabantchik ZI. Repression of ferritin expression modulates cell responsiveness to H-ras-induced growth. Biochem Soc Trans 2002; 30 (4): 777–780. doi: 10.1042.
78. O‘Donnell KA, Yu D, Zeller KI et al. Activation of transferrin receptor 1 by c-Myc enhances cellular proliferation and tumorigenesis. Mol Cell Biol 2006; 26 (6): 2373–2386. doi: 10.1128/MCB.26.6.2373-2386.2006.
79. Wu KJ, Polack A, Dalla-Favera R. Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC. Science 1999; 283 (5402): 676–679.
80. Hangauer MJ, Viswanathan VS, Ryan MJ et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 2017; 551 (7679): 247–250. doi: 10.1038/nature24297.
81. 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 (7): 1990–2000. doi: 10.1158/1078-0432.CCR-13-2805.
82. Miess H, Dankworth B, Gouw AM et al. The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma. Oncogene. In press 2018. doi: 10.1038/s41388-018-0315-z.
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