Research progress on radiobiological effects of ferroptosis in cancer
Wang Tianxiang1,2, Du Mingyu1, Zhang Pingchuan1,2, Yin Li1,2,3, He Xia1,2,3
1The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China; 2The Fourth Clinical Medical College of Nanjing Medical University, Nanjing 210000, China; 3The Collaborative Innovation Center for Cancer Personalized Medicine of Nanjing Medical University, Nanjing 210000, China
Abstract：Ferroptosis is a new form of regulated cell death discovered in recent years, which is iron-dependent cell death characterized by peroxidation of polyunsaturated fatty acid phospholipids. Recent studies have shown that radiotherapy can induce ferroptosis in cancer cells via ionizing radiation. Targeting ferroptosis plays a synergistic role in tumor suppression with radiation, which not only further deepens the connotation of radiobiology, but also provides a new perspective for tumor radiosensitization. This review systematically summarizes the occurrence and defense of ferroptosis, focusing on the key role of ferroptosis in the radiobiological effects of tumor cells and the potential application of ferroptosis in radiosensitization.
Wang Tianxiang,Du Mingyu,Zhang Pingchuan et al. Research progress on radiobiological effects of ferroptosis in cancer[J]. Chinese Journal of Radiation Oncology, 2023, 32(8): 743-747.
[1] Barker HE, Paget JT, Khan AA, et al.The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence[J]. Nat Rev Cancer, 2015,15(7):409-425. DOI: 10.1038/nrc3958. [2] Ross GM.Induction of cell death by radiotherapy[J]. Endocr Relat Cancer, 1999,6(1):41-44. DOI: 10.1677/erc.0.0060041. [3] Dixon SJ, Lemberg KM, Lamprecht MR, et al.Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012,149(5):1060-1072. DOI: 10.1016/j.cell.2012.03.042. [4] Lei G, Zhang Y, Koppula P, et al.The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression[J]. Cell Res, 2020,30(2):146-162. DOI: 10.1038/s41422-019-0263-3. [5] Lang X, Green MD, Wang W, et al.Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11[J]. Cancer Discov, 2019,9(12):1673-1685. DOI: 10.1158/2159-8290.CD-19-0338. [6] Conrad M, Pratt DA.The chemical basis of ferroptosis[J]. Nat Chem Biol, 2019,15(12):1137-1147. DOI: 10.1038/s41589-019-0408-1. [7] Gan B.Mitochondrial regulation of ferroptosis[J]. J Cell Biol, 2021,220(9):e202105043. DOI: 10.1083/jcb.202105043. [8] Lei G, Zhuang L, Gan BY.Targeting ferroptosis as a vulnerability in cancer[J]. Nat Rev Cancer, 2022,22(7):381-396. DOI: 10.1038/s41568-022-00459-0. [9] Dixon SJ, Patel DN, Welsch M, et al.Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis[J]. Elife, 2014,3:e02523. DOI: 10.7554/eLife.02523. [10] Yang WS, SriRamaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4[J]. Cell, 2014,156(1-2):317-331. DOI: 10.1016/j.cell.2013.12.010. [11] Wang LY, Liu YC, Du TT, et al.ATF3 promotes erastin-induced ferroptosis by suppressing system Xc()[J]. Cell Death Differ, 2020,27(2):662-675. DOI: 10.1038/s41418-019-0380-z. [12] Habib E, Linher-Melville K, Lin HX, et al.Expression of xCT and activity of system xc(-) are regulated by NRF2 in human breast cancer cells in response to oxidative stress[J]. Redox Biol, 2015,5:33-42. DOI: 10.1016/j.redox.2015.03.003. [13] Chen D, Fan Z, Rauh M, et al.ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner[J]. Oncogene, 2017,36(40):5593-5608. DOI: 10.1038/onc.2017.146. [14] Ishimoto T, Nagano O, Yae T, et al.CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth[J]. Cancer Cell, 2011,19(3):387-400. DOI: 10.1016/j.ccr.2011.01.038. [15] Ingold I, Berndt C, Schmitt S, et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis[J]. Cell, 2018,172(3):409-422.e21. DOI: 10.1016/j.cell.2017.11.048. [16] Bersuker K, Hendricks JM, Li Z, et al.The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis[J]. Nature, 2019,575(7784):688-692. DOI: 10.1038/s41586-019-1705-2. [17] Koppula P, Lei G, Zhang YL, et al.A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers[J]. Nat Commun, 2022,13(1):2206. DOI: 10.1038/s41467-022-29905-1. [18] Kraft V, Bezjian CT, Pfeiffer S, et al.GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling[J]. ACS Cent Sci, 2020,6(1):41-53. DOI: 10.1021/acscentsci.9b01063. [19] Soula M, Weber RA, Zilka O, et al.Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers[J]. Nat Chem Biol, 2020,16(12):1351-1360. DOI: 10.1038/s41589-020-0613-y. [20] Mao C, Liu XG, Zhang YL, et al.DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer[J]. Nature, 2021,593(7860):586-590. DOI: 10.1038/s41586-021-03539-7. [21] Azzam EI, Jay-Gerin JP, Pain D.Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury[J]. Cancer Lett, 2012,327(1-2):48-60. DOI: 10.1016/j.canlet.2011.12.012. [22] Chen PH, Wu J, Ding CC, et al.Kinome screen of ferroptosis reveals a novel role of ATM in regulating iron metabolism[J]. Cell Death Differ, 2020,27(3):1008-1022. DOI: 10.1038/s41418-019-0393-7. [23] Lei G, Zhang YL, Hong T, et al.Ferroptosis as a mechanism to mediate p53 function in tumor radiosensitivity[J]. Oncogene, 2021,40(20):3533-3547. DOI: 10.1038/s41388-021-01790-w. [24] Xie YC, Zhu S, Song XX, et al.The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity[J]. Cell Rep, 2017,20(7):1692-1704. DOI: 10.1016/j.celrep.2017.07.055. [25] Song XX, Zhu S, Chen P, et al. AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system Xc- Activity[J]. Curr Biol, 2018,28(15):2388-2399.e5. DOI: 10.1016/j.cub.2018.05.094. [26] Lee H, Zandkarimi F, Zhang YL, et al.Energy- stress-mediated AMPK activation inhibits ferroptosis[J]. Nat Cell Biol, 2020,22(2):225-234. DOI: 10.1038/s41556-020-0461-8. [27] Wang WM, Green M, Choi JE, et al.CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy[J]. Nature, 2019,569(7755):270-274. DOI: 10.1038/s41586-019-1170-y. [28] Liu J, Kuang FM, Kroemer G, et al.Autophagy-dependent ferroptosis: machinery and regulation[J]. Cell Chem Biol, 2020,27(4):420-435. DOI: 10.1016/j.chembiol.2020.02.005. [29] Zheng XG, Liu BT, Liu XX, et al.PERK regulates the sensitivity of hepatocellular carcinoma cells to high-LET carbon ions via either apoptosis or ferroptosis[J]. J Cancer, 2022,13(2):669-680. DOI: 10.7150/jca.61622. [30] Liao P, Wang WM, Wang WC, et al. CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4[J]. Cancer Cell, 2022,40(4):365-378.e6. DOI: 10.1016/j.ccell.2022.02.003. [31] Deng JJ, Zhou M, Liao TT, et al.Targeting cancer cell ferroptosis to reverse immune checkpoint inhibitor therapy resistance[J]. Front Cell Dev Biol, 2022,10:818453. DOI: 10.3389/fcell.2022.818453. [32] Xu SH, Chaudhary O, Rodríguez-Morales P, et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors[J]. Immunity, 2021,54(7):1561-1577.e7. DOI: 10.1016/j.immuni.2021.05.003. [33] Singhal R, Mitta SR, Das NK, et al.HIF-2α activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron[J]. J Clin Invest, 2021,131(12):e143691. DOI: 10.1172/JCI143691. [34] Ye LF, Chaudhary KR, Zandkarimi F, et al.Radiation- induced lipid peroxidation triggers ferroptosis and synergizes with ferroptosis inducers[J]. ACS Chem Biol, 2020,15(2):469-484. DOI: 10.1021/acschembio.9b00939. [35] Ye L, Jin FY, Kumar SK, et al.The mechanisms and therapeutic targets of ferroptosis in cancer[J]. Expert Opin Ther Targets, 2021,25(11):965-986. DOI: 10.1080/14728222.2021.2011206. [36] Zhang YG, Tan Y, Liu SC, et al.Implications of Withaferin A for the metastatic potential and drug resistance in hepatocellular carcinoma cells via Nrf2-mediated EMT and ferroptosis[J]. Toxicol Mech Methods, 2023,33(1):47-55. DOI: 10.1080/15376516.2022.2075297. [37] Shan XZ, Li SM, Sun BJ, et al.Ferroptosis-driven nanotherapeutics for cancer treatment[J]. J Control Release, 2020,319:322-332. DOI: 10.1016/j.jconrel.2020.01.008. [38] Luo YJ, Huang QM, He B, et al.Regulation of ferroptosis by non‑coding RNAs in the development and treatment of cancer (Review)[J]. Oncol Rep, 2021,45(1):29-48. DOI: 10.3892/or.2020.7836. [39] Li X, Duan LJ, Yuan SJ, et al.Ferroptosis inhibitor alleviates Radiation-induced lung fibrosis (RILF) via down-regulation of TGF-β1[J]. J Inflamm (Lond), 2019,16:11. DOI: 10.1186/s12950-019-0216-0. [40] Li L, Wu DM, Deng SH, et al.NVP-AUY922 alleviates radiation-induced lung injury via inhibition of autophagy-dependent ferroptosis[J]. Cell Death Discov, 2022,8(1):86. DOI: 10.1038/s41420-022-00887-9.
2023, Vol. 32 
