Ferroptosis, radiotherapy, and combination therapeutic strategies

doi:10.1007/s13238-021-00841-y

Protein Cell

2021, Vol. 12

Issue (11) : 836-857 https://doi.org/10.1007/s13238-021-00841-y

REVIEW

Ferroptosis, radiotherapy, and combination therapeutic strategies

Guang Lei^1,², Chao Mao², Yuelong Yan², Li Zhuang², Boyi Gan^2,³(

)

¹. Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China
². 2Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
³. The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA

Download: PDF(2124 KB)
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

Abstract

Ferroptosis, an iron-dependent form of regulated cell death driven by peroxidative damages of polyunsaturated-fatty-acid-containing phospholipids in cellular membranes, has recently been revealed to play an important role in radiotherapy-induced cell death and tumor suppression, and to mediate the synergy between radiotherapy and immunotherapy. In this review, we summarize known as well as putative mechanisms underlying the crosstalk between radiotherapy and ferroptosis, discuss the interactions between ferroptosis and other forms of regulated cell death induced by radiotherapy, and explore combination therapeutic strategies targeting ferroptosis in radiotherapy and immunotherapy. This review will provide important frameworks for future investigations of ferroptosis in cancer therapy.

Keywords ferroptosis lipid peroxidation GPX4 SLC7A11 radiotherapy immunotherapy radiosensitization combination therapy

Corresponding Author(s): Boyi Gan

Online First Date: 21 May 2021 Issue Date: 01 December 2021

Cite this article:

Guang Lei,Chao Mao,Yuelong Yan, et al. Ferroptosis, radiotherapy, and combination therapeutic strategies[J]. Protein Cell, 2021, 12(11): 836-857.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-021-00841-y
https://academic.hep.com.cn/pac/EN/Y2021/V12/I11/836

1	S Adjemian, T Oltean, S Martens, B Wiernicki, V Goossens, TV Berghe, B Cappe, M Ladik, FB Riquet, L Heyndrickx (2020) Ionizing radiation results in a mixture of cellular outcomes including mitotic catastrophe, senescence, methuosis, and iron-dependent cell death. Cell Death Dis 11:1–15 https://doi.org/10.1038/s41419-020-03209-y
2	I Alim, JT Caulfield, Y Chen, V Swarup, DH Geschwind, E Ivanova, J Seravalli, Y Ai, LH Sansing, EJS Marie (2019) Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke. Cell 177(1262–1279): https://doi.org/10.1016/j.cell.2019.03.032
3	SW Alvarez, VO Sviderskiy, EM Terzi, T Papagiannakopoulos, AL Moreira, S Adams, DM Sabatini, K Birsoy, R Possemato (2017) NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 551:639–643 https://doi.org/10.1038/nature24637
4	GJ Anderson, CD Vulpe (2009) Mammalian iron transport. Cell Mol Life Sci 66:3241 https://doi.org/10.1007/s00018-009-0051-1
5	JPF Angeli, M Conrad (2018) Selenium and GPX4, a vital symbiosis. Free Radical Biol Med 127:153–159 https://doi.org/10.1016/j.freeradbiomed.2018.03.001
6	JPF Angeli, M Schneider, B Proneth, YY Tyurina, VA Tyurin, VJ Hammond, N Herbach, M Aichler, A Walch, E Eggenhofer (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16:1180–1191 https://doi.org/10.1038/ncb3064
7	BJ Aubrey, GL Kelly, A Janic, MJ Herold, A Strasser (2018) How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ 25:104–113 https://doi.org/10.1038/cdd.2017.169
8	A Ayala, MF Muñoz, S Argüelles (2014). Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longevity https://doi.org/10.1155/2014/360438
9	EI Azzam, J-P Jay-Gerin, D Pain (2012) Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury. Cancer Lett 327:48–60 https://doi.org/10.1016/j.canlet.2011.12.012
10	MA Badgley, DM Kremer, HC Maurer, KE DelGiorno, H-J Lee, V Purohit, IR Sagalovskiy, A Ma, J Kapilian, CE Firl (2020) Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 368:85–89 https://doi.org/10.1126/science.aaw9872
11	KE Baidoo, K Yong, MW Brechbiel (2013) Molecular pathways: targeted α-particle radiation therapy. Clin Cancer Res 19:530–537 https://doi.org/10.1158/1078-0432.CCR-12-0298
12	MF Benveniste, D Gomez, BW Carter, SL Betancourt Cuellar, GS Shroff, APA Benveniste, EG Odisio, EM Marom (2019) Recognizing radiation therapy-related complications in the chest. Radiographics 39:344–366 https://doi.org/10.1148/rg.2019180061
13	M Berbee, Q Fu, M Boerma, R Pathak, D Zhou, KS Kumar, M Hauer-Jensen (2011) Reduction of radiation-induced vascular nitrosative stress by the vitamin E analog γ-tocotrienol: evidence of a role for tetrahydrobiopterin. Int J Radiat Oncol Biol Phys 79:884–891 https://doi.org/10.1016/j.ijrobp.2010.08.032
14	K Bersuker, J Hendricks, Z Li, L Magtanong, B Ford, PH Tang, MA Roberts, B Tong, TJ Maimone, R Zoncu (2019) The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575:688 https://doi.org/10.1038/s41586-019-1705-2
15	KT Bieging, SS Mello, LD Attardi (2014) Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer 14:359–370 https://doi.org/10.1038/nrc3711
16	S Boumahdi, FJ de Sauvage (2020) The great escape: tumour cell plasticity in resistance to targeted therapy. Nat Rev Drug Discov 19:39–56 https://doi.org/10.1038/s41573-019-0044-1
17	M Braig, S Lee, C Loddenkemper, C Rudolph, AH Peters, B Schlegelberger, H Stein, B Dörken, T Jenuwein, CA Schmitt (2005) Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436:660–665 https://doi.org/10.1038/nature03841
18	ML Bristol, X Di, MJ Beckman, EN Wilson, SC Henderson, A Maiti, Z Fan, DA Gewirtz (2012) Dual functions of autophagy in the response of breast tumor cells to radiation: cytoprotective autophagy with radiation alone and cytotoxic autophagy in radiosensitization by vitamin D3. Autophagy 8:739–753 https://doi.org/10.4161/auto.19313
19	CW Brown, JJ Amante, P Chhoy, AL Elaimy, H Liu, LJ Zhu, CE Baer, SJ Dixon, AM Mercurio (2019) Prominin2 drives ferroptosis resistance by stimulating iron export. Dev Cell 51(575–586): https://doi.org/10.1016/j.devcel.2019.10.007
20	EA Bump, JM Brown (1990) Role of glutathione in the radiation response of mammalian cells invitro and in vivo. Pharmacol Ther 47:117–136 https://doi.org/10.1016/0163-7258(90)90048-7
21	AK Cheema, R Pathak, F Zandkarimi, P Kaur, L Alkhalil, R Singh, X Zhong, S Ghosh, N Aykin-Burns, M Hauer-Jensen (2014) Liver metabolomics reveals increased oxidative stress and fibrogenic potential in gfrp transgenic mice in response to ionizing radiation. J Proteome Res 13:3065–3074 https://doi.org/10.1021/pr500278t
22	C-Y Chen, JD Oliner, Q Zhan, AJ Fornace, B Vogelstein, MB Kastan (1994) Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway. Proc Natl Acad Sci 91:2684–2688 https://doi.org/10.1073/pnas.91.7.2684
23	D Chen, Z Fan, M Rauh, M Buchfelder, I Eyupoglu, N Savaskan (2017a) ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner. Oncogene 36:5593–5608 https://doi.org/10.1038/onc.2017.146
24	D Chen, O Tavana, B Chu, L Erber, Y Chen, R Baer, W Gu (2017b) NRF2 is a major target of ARF in p53-independent tumor suppression. Mol Cell 68(224–232): https://doi.org/10.1016/j.molcel.2017.09.009
25	P-H Chen, J Wu, C-KC Ding, C-C Lin, S Pan, N Bossa, Y Xu, W-H Yang, B Mathey-Prevot, J-T Chi (2020) Kinome screen of ferroptosis reveals a novel role of ATM in regulating iron metabolism. Cell Death Differ 27:1008–1022 https://doi.org/10.1038/s41418-019-0393-7
26	SH Chew, Y Okazaki, S Akatsuka, S Wang, L Jiang, Y Ohara, F Ito, H Saya, Y Sekido, S Toyokuni (2017) Rheostatic CD44 isoform expression and its association with oxidative stress in human malignant mesothelioma. Free Radical Biol Med 106:91–99 https://doi.org/10.1016/j.freeradbiomed.2017.02.011
27	IIC Chio, DA Tuveson (2017) ROS in cancer: the burning question. Trends Mol Med 23:411–429 https://doi.org/10.1016/j.molmed.2017.03.004
28	S Choudhary, SC Burns, H Mirsafian, W Li, DT Vo, M Qiao, X Lei, AD Smith, LO Penalva (2020) Genomic analyses of early responses to radiation inglioblastoma reveal new alterations at transcription, splicing, and translation levels. Sci Rep 10:1–12 https://doi.org/10.1038/s41598-020-69585-9
29	B Chu, N Kon, D Chen, T Li, T Liu, L Jiang, S Song, O Tavana, W Gu (2019) ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nat Cell Biol 21:579–591 https://doi.org/10.1038/s41556-019-0305-6
30	SM Colles, GM Chisolm (2000) Lysophosphatidylcholine-induced cellular injury in cultured fibroblasts involves oxidative events. J Lipid Res 41:1188–1198 https://doi.org/10.1016/S0022-2275(20)33425-8
31	M Conrad, DA Pratt (2019) The chemical basis of ferroptosis. Nat Chem Biol 15:1137–1147 https://doi.org/10.1038/s41589-019-0408-1
32	M Conrad, B Proneth (2020) Selenium: tracing another essential element of ferroptotic cell death. Cell Chem Biol https://doi.org/10.1016/j.chembiol.2020.03.012
33	M Conrad, H Sato (2012) The oxidative stress-inducible cystine/glutamate antiporter, system x c−: cystine supplier and beyond. Amino Acids 42:231–246 https://doi.org/10.1007/s00726-011-0867-5
34	MJ Crabtree, AL Tatham, AB Hale, NJ Alp, KM Channon (2009) Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling relative importance of the de novo biopterin synthesis versus salvage pathways. J Biol Chem 284:28128–28136 https://doi.org/10.1074/jbc.M109.041483
35	MR de la Vega, E Chapman, DD Zhang (2018) NRF2 and the hallmarks of cancer. Cancer Cell 34:21–43 https://doi.org/10.1016/j.ccell.2018.03.022
36	G Delaney, S Jacob, C Featherstone, M Barton (2005) The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer 104:1129–1137 https://doi.org/10.1002/cncr.21324
37	SJ Dixon, KM Lemberg, MR Lamprecht, R Skouta, EM Zaitsev, CE Gleason, DN Patel, AJ Bauer, AM Cantley, WS Yang (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149:1060–1072 https://doi.org/10.1016/j.cell.2012.03.042
38	SJ Dixon, DN Patel, M Welsch, R Skouta, ED Lee, M Hayano, AG Thomas, CE Gleason, NP Tatonetti, BS Slusher (2014) Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 3: https://doi.org/10.7554/eLife.02523
39	SJ Dixon, GE Winter, LS Musavi, ED Lee, B Snijder, M Rebsamen, G Superti-Furga, BR Stockwell (2015) Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol 10:1604–1609 https://doi.org/10.1021/acschembio.5b00245
40	S Doll, B Proneth, YY Tyurina, E Panzilius, S Kobayashi, I Ingold, M Irmler, J Beckers, M Aichler, A Walch (2017) ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol 13:91–98 https://doi.org/10.1038/nchembio.2239
41	S Doll, FP Freitas, R Shah, M Aldrovandi, MC da Silva, I Ingold, AG Grocin, TNX da Silva, E Panzilius, C Scheel (2019) FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 575:693 https://doi.org/10.1038/s41586-019-1707-0
42	K Duberley, S Heales, A Abramov, A Chalasani, J Land, S Rahman, I Hargreaves (2014) Effect of Coenzyme Q10 supplementation on mitochondrial electron transport chain activity and mitochondrial oxidative stress in Coenzyme Q10 deficient human neuronal cells. Int J Biochem Cell Biol 50:60–63 https://doi.org/10.1016/j.biocel.2014.02.003
43	MM Elguindy, E Nakamaru-Ogiso (2015) Apoptosis-inducing factor (AIF) and its family member protein, AMID, are rotenonesensitive NADH: ubiquinone oxidoreductases (NDH-2). J Biol Chem 290:20815–20826 https://doi.org/10.1074/jbc.M115.641498
44	Z Fan, A Wirth, D Chen, C Wruck, M Rauh, M Buchfelder, N Savaskan (2017) Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis 6:e371–e371 https://doi.org/10.1038/oncsis.2017.65
45	P Fei, WS El-Deiry (2003) P53 and radiation responses. Oncogene 22:5774–5783 https://doi.org/10.1038/sj.onc.1206677
46	H Feng, K Schorpp, J Jin, CE Yozwiak, BG Hoffstrom, AM Decker, P Rajbhandari, ME Stokes, HG Bender, JM Csuka (2020) Transferrin receptor is a specific ferroptosis marker. Cell Rep 30(3411–3423): https://doi.org/10.1016/j.celrep.2020.02.049
47	B Frei, MC Kim, BN Ames (1990) Ubiquinol-10 is an effective lipidsoluble antioxidant at physiological concentrations. Proc Natl Acad Sci 87:4879–4883 https://doi.org/10.1073/pnas.87.12.4879
48	L Galluzzi, I Vitale, SA Aaronson, JM Abrams, D Adam, P Agostinis, ES Alnemri, L Altucci, I Amelio, DW Andrews (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 25:486–541 https://doi.org/10.1038/s41418-017-0012-4
49	M Gao, P Monian, N Quadri, R Ramasamy, X Jiang (2015) Glutaminolysis and transferrin regulate ferroptosis. Mol Cell 59:298–308 https://doi.org/10.1016/j.molcel.2015.06.011
50	M Gao, P Monian, Q Pan, W Zhang, J Xiang, X Jiang (2016) Ferroptosis is an autophagic cell death process. Cell Res 26:1021–1032 https://doi.org/10.1038/cr.2016.95
51	J Garcia-Bermudez, L Baudrier, EC Bayraktar, Y Shen, K La, R Guarecuco, B Yucel, D Fiore, B Tavora, E Freinkman (2019) Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death. Nature 567:118–122 https://doi.org/10.1038/s41586-019-0945-5
52	N Geng, B Shi, S Li, Z Zhong, Y Li, W Xua, H Zhou, J Cai (2018) Knockdown of ferroportin accelerates erastin-induced ferroptosis in neuroblastoma cells. Eur Rev Med Pharmacol Sci 22:3826–3836
53	AG Georgakilas, OA Martin, WM Bonner (2017) p21: a two-faced genome guardian. Trends Mol Med 23:310–319 https://doi.org/10.1016/j.molmed.2017.02.001
54	DR Green (2019) The coming decade of cell death research: five riddles. Cell 177:1094–1107 https://doi.org/10.1016/j.cell.2019.04.024
55	AV Gudkov, EA Komarova (2003) The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer 3:117–129 https://doi.org/10.1038/nrc992
56	J Guo, B Xu, Q Han, H Zhou, Y Xia, C Gong, X Dai, Z Li, G Wu(2018) Ferroptosis: a novel anti-tumor action for cisplatin. Cancer Res Treat 50:445 https://doi.org/10.4143/crt.2016.572
57	E Habib, K Linher-Melville, H-X Lin, G Singh (2015) Expression of xCT and activity of system xc− are regulated by NRF2 in human breast cancer cells in response to oxidative stress. Redox Biol 5:33–42 https://doi.org/10.1016/j.redox.2015.03.003
58	Y Han, A Platonov, M Akhalaia, Y-S Yun, J-Y Song (2005) Differential effect of γ-radiation-induced heme oxygenase-1 activity in female and male C57BL/6 mice. J Korean Med Sci 20:535–541 https://doi.org/10.3346/jkms.2005.20.4.535
59	D Hanahan, RA Weinberg (2011) Hallmarks of cancer: the next generation. Cell 144:646–674 https://doi.org/10.1016/j.cell.2011.02.013
60	MJ Hangauer, VS Viswanathan, MJ Ryan, D Bole, JK Eaton, A Matov, J Galeas, HD Dhruv, ME Berens, SL Schreiber (2017) Drugtolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551:247–250 https://doi.org/10.1038/nature24297
61	B Hassannia, B Wiernicki, I Ingold, F Qu, S Van Herck, YY Tyurina, H Bayır, BA Abhari, JPF Angeli, SM Choi (2018) Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J Clin Investig 128:3341–3355 https://doi.org/10.1172/JCI99032
62	B Hassannia, P Vandenabeele, TV Berghe (2019) Targeting ferroptosis to iron out cancer. Cancer Cell 35:830–849 https://doi.org/10.1016/j.ccell.2019.04.002
63	M Hayano, W Yang, C Corn, N Pagano, B Stockwell (2016) Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ 23:270–278 https://doi.org/10.1038/cdd.2015.93
64	FG Herrera, J Bourhis, G Coukos (2017) Radiotherapy combination opportunities leveraging immunity for the next oncology practice. Cancer J Clin 67:65–85 https://doi.org/10.3322/caac.21358
65	N Horikoshi, J Cong, N Kley, T Shenk (1999) Isolation of differentially expressed cDNAs from p53-dependent apoptotic cells: activation of the human homologue of the Drosophila peroxidasin gene. Biochem Biophys Res Commun 261:864–869 https://doi.org/10.1006/bbrc.1999.1123
66	W Hou, Y Xie, X Song, X Sun, MT Lotze, HJ III Zeh, R Kang, D Tang (2016) Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 12:1425–1428 https://doi.org/10.1080/15548627.2016.1187366
67	W Hu, C Zhang, R Wu, Y Sun, A Levine, Z Feng (2010) Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci 107:7455–7460 https://doi.org/10.1073/pnas.1001006107
68	L Hu, H Wang, L Huang, Y Zhao, J Wang (2016) Crosstalk between autophagy and intracellular radiation response. Int J Oncol 49:2217–2226 https://doi.org/10.3892/ijo.2016.3719
69	K Hu, K Li, J Lv, J Feng, J Chen, H Wu, F Cheng, W Jiang, J Wang, H Pei (2020) Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma. J Clin Invest 130:1752 https://doi.org/10.1172/JCI124049
70	R-X Huang, P-K Zhou (2020) DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transd Target Therapy 5:1–27 https://doi.org/10.1038/s41392-020-0150-x
71	PM Hwang, F Bunz, J Yu, C Rago, TA Chan, MP Murphy, GF Kelso, RA Smith, KW Kinzler, B Vogelstein (2001) Ferredoxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells. Nat Med 7:1111–1117 https://doi.org/10.1038/nm1001-1111
72	I Ingold, C Berndt, S Schmitt, S Doll, G Poschmann, K Buday, A Roveri, X Peng, FP Freitas, T Seibt (2018) Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell 172(409–422): https://doi.org/10.1016/j.cell.2017.11.048
73	T Ishimoto, O Nagano, T Yae, M Tamada, T Motohara, H Oshima, M Oshima, T Ikeda, R Asaba, H Yagi (2011) CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc− and thereby promotes tumor growth. Cancer Cell 19:387–400 https://doi.org/10.1016/j.ccr.2011.01.038
74	DA Jaffray (2012) Image-guided radiotherapy: from current concept to future perspectives. Nat Rev Clin Oncol 9:688 https://doi.org/10.1038/nrclinonc.2012.194
75	L Jiang, N Kon, T Li, S-J Wang, T Su, H Hibshoosh, R Baer, W Gu (2015) Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520:57–62 https://doi.org/10.1038/nature14344
76	VE Kagan, G Mao, F Qu, JPF Angeli, S Doll, C St Croix, HH Dar, B Liu, VA Tyurin, VB Ritov (2017) Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 13:81–90 https://doi.org/10.1038/nchembio.2238
77	Y Kaku, A Tsuchiya, T Kanno, T Nishizaki (2015) HUHS1015 induces necroptosis and caspase-independent apoptosis of MKN28human gastric cancer cells in association with AMID accumulation in the nucleus. Anti-Cancer Agents Med Chem 15:242–247 https://doi.org/10.2174/1871520614666140922122700
78	WW-Y Kam, RB Banati (2013) Effects of ionizing radiation on mitochondria. Free Radical Biol Med 65:607–619 https://doi.org/10.1016/j.freeradbiomed.2013.07.024
79	R Kang, D Tang (2016) What is the pathobiology of inflammation to cell death? Apoptosis, necrosis, necroptosis, autophagic cell death, pyroptosis, and NETosis. In: Autophagy networks in inflammation. Springer, Berlin, pp 81–106 https://doi.org/10.1007/978-3-319-30079-5_5
80	R Kang, G Kroemer, D Tang (2019) The tumor suppressor protein p53 and the ferroptosis network. Free Radical Biol Med 133:162–168 https://doi.org/10.1016/j.freeradbiomed.2018.05.074
81	SE Kim, L Zhang, K Ma, M Riegman, F Chen, I Ingold, M Conrad, MZ Turker, M Gao, X Jiang (2016) Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nat Nanotechnol 11:977 https://doi.org/10.1038/nnano.2016.164
82	P Koppula, Y Zhang, L Zhuang, B Gan (2018) Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer Commun 38:1–13 https://doi.org/10.1186/s40880-018-0288-x
83	P Koppula, L Zhuang, B Gan (2020) Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell. https://doi.org/10.1007/s13238-020-00789-5
84	T Kordbacheh, J Honeychurch, F Blackhall, C Faivre-Finn, T Illidge (2018) Radiotherapy and anti-PD-1/PD-L1 combinations in lung cancer: building better translational research platforms. Ann Oncol 29:301–310 https://doi.org/10.1093/annonc/mdx790
85	VA Kraft, CT Bezjian, S Pfeiffer, L Ringelstetter, C Müller, F Zandkarimi, J Merl-Pham, X Bao, N Anastasov, J Kössl (2019) GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Central Sci 6:41–53 https://doi.org/10.1021/acscentsci.9b01063
86	X Lang, MD Green, W Wang, J Yu, JE Choi, L Jiang, P Liao, J Zhou, Q Zhang, A Dow (2019) Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov 9:1673–1685 https://doi.org/10.1158/2159-8290.CD-19-0338
87	JK Leach, G Van Tuyle, P-S Lin, R Schmidt-Ullrich, RB Mikkelsen (2001) Ionizing radiation-induced, mitochondria-dependent generation of reactive oxygen/nitrogen. Cancer Res 61:3894–3901
88	H Lee, F Zandkarimi, Y Zhang, JK Meena, J Kim, L Zhuang, S Tyagi, L Ma, TF Westbrook, GR Steinberg (2020) Energy-stressmediated AMPK activation inhibits ferroptosis. Nat Cell Biol 22:225–234 https://doi.org/10.1038/s41556-020-0461-8
89	G Lei, Y Zhang, P Koppula, X Liu, J Zhang, SH Lin, JA Ajani, Q Xiao, Z Liao, H Wang (2020) The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res 30:146–162 https://doi.org/10.1038/s41422-019-0263-3
90	L Li, A Rezvan, JC Salerno, A Husain, K Kwon, H Jo, DG Harrison, W Chen (2010) GTP cyclohydrolase I phosphorylation and interaction with GTP cyclohydrolase feedback regulatory protein provide novel regulation of endothelial tetrahydrobiopterin and nitric oxide. Circ Res 106:328–336 https://doi.org/10.1161/CIRCRESAHA.109.210658
91	M Li, L You, J Xue, Y Lu (2018) Ionizing radiation-induced cellular senescence in normal, non-transformed cells and the involved DNA damage response: a mini review. Front Pharmacol 9:522 https://doi.org/10.3389/fphar.2018.00522
92	X Li, L Duan, S Yuan, X Zhuang, T Qiao, J He (2019a) Ferroptosis inhibitor alleviates radiation-induced lung fibrosis (RILF) via down-regulation of TGF-β1. J Inflamm 16:11 https://doi.org/10.1186/s12950-019-0216-0
93	X Li, X Zhuang, T Qiao (2019b) Role of ferroptosis in the process of acute radiation-induced lung injury in mice. Biochem Biophys Res Commun 519:240–245 https://doi.org/10.1016/j.bbrc.2019.08.165
94	C Li, X Dong, W Du, X Shi, K Chen, W Zhang, M Gao (2020) LKB1-AMPK axis negatively regulates ferroptosis by inhibiting fatty acid synthesis. Signal Transd Target Ther 5:1–4 https://doi.org/10.1038/s41392-019-0089-y
95	C Liang, X Zhang, M Yang, X Dong (2019) Recent progress in ferroptosis inducers for cancer therapy. Adv Mater 31:1904197 https://doi.org/10.1002/adma.201904197
96	B Liu, J Yi, X Yang, L Liu, X Lou, Z Zhang, H Qi, Z Wang, J Zou, W-G Zhu (2019a) MDM2-mediated degradation of WRN promotes cellular senescence in a p53-independent manner. Oncogene 38:2501–2515 https://doi.org/10.1038/s41388-018-0605-5
97	T Liu, L Jiang, O Tavana, W Gu (2019b) The deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Res 79:1913–1924 https://doi.org/10.1158/0008-5472.CAN-18-3037
98	J Liu, F Kuang, G Kroemer, DJ Klionsky, R Kang, D Tang (2020a) Autophagy-dependent ferroptosis: machinery and regulation. Cell Chem Biol 27:420 https://doi.org/10.1016/j.chembiol.2020.02.005
99	J Liu, Z Zhu, Y Liu, L Wei, B Li, F Mao, J Zhang, Y Wang, Y Liu (2020b) MDM2 inhibition-mediated autophagy contributes to the pro-apoptotic effect of berberine in p53-null leukemic cells. Life Sci 242: https://doi.org/10.1016/j.lfs.2019.117228
100	X Liu, K Olszewski, Y Zhang, EW Lim, J Shi, X Zhang, J Zhang, H Lee, P Koppula, G Lei (2020c) Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer. Nat Cell Biol 22:476–486 https://doi.org/10.1038/s41556-020-0496-x
101	X Liu, Y Zhang, L Zhuang, K Olszewski, B Gan (2020d) NADPH debt drives redox bankruptcy: SLC7A11/xCT-mediated cystine uptake as a double-edge sword in cellular redox regulation. Genes Dis. https://doi.org/10.1016/j.gendis.2020.11.010
102	C Louandre, I Marcq, H Bouhlal, E Lachaier, C Godin, Z Saidak, C François, D Chatelain, V Debuysscher, J-C Barbare (2015) The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells. Cancer Lett 356:971–977 https://doi.org/10.1016/j.canlet.2014.11.014
103	S Ma, E Henson, Y Chen, S Gibson (2016) Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells. Cell Death Dis 7:e2307–e2307 https://doi.org/10.1038/cddis.2016.208
104	L Magtanong, P-J Ko, M To, JY Cao, GC Forcina, A Tarangelo, CC Ward, K Cho, GJ Patti, DK Nomura (2019) Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem Biol 26(420–432): https://doi.org/10.1016/j.chembiol.2018.11.016
105	P Maier, L Hartmann, F Wenz, C Herskind (2016) Cellular pathways in response to ionizing radiation and their targetability for tumor radiosensitization. Int J Mol Sci 17:102 https://doi.org/10.3390/ijms17010102
106	J Malhotra, SK Jabbour, J Aisner (2017) Current state of immunotherapy for non-small cell lung cancer. Transl Lung Cancer Res 6:196 https://doi.org/10.21037/tlcr.2017.03.01
107	KR Marshall, M Gong, L Wodke, JH Lamb, DJ Jones, PB Farmer, NS Scrutton, AW Munro (2005) The human apoptosis-inducing protein AMID is an oxidoreductase with a modified flavin cofactor and DNA binding activity. J Biol Chem 280:30735–30740 https://doi.org/10.1074/jbc.M414018200
108	R Maya, M Balass, S-T Kim, D Shkedy, J-FM Leal, O Shifman, M Moas, T Buschmann, ZE Ronai, Y Shiloh (2001) ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev 15:1067–1077 https://doi.org/10.1101/gad.886901
109	EA McCullagh, DE Featherstone (2014) Behavioral characterization of system xc-mutant mice. Behav Brain Res 265:1–11 https://doi.org/10.1016/j.bbr.2014.02.010
110	JT McDonald, K Kim, AJ Norris, E Vlashi, TM Phillips, C Lagadec, L Della Donna, J Ratikan, H Szelag, L Hlatky (2010) Ionizing radiation activates the Nrf2 antioxidant response. Cancer Res 70:8886–8895 https://doi.org/10.1158/0008-5472.CAN-10-0171
111	M Mijit, V Caracciolo, A Melillo, F Amicarelli, A Giordano (2020) Role of p53 in the regulation of cellular senescence. Biomolecules 10:420 https://doi.org/10.3390/biom10030420
112	O Mohamad, T Tabuchi, Y Nitta, A Nomoto, A Sato, G Kasuya, H Makishima, H Choy, S Yamada, T Morishima (2019) Risk of subsequent primary cancers after carbon ion radiotherapy, photon radiotherapy, or surgery for localised prostate cancer: a propensity score-weighted, retrospective, cohort study. Lancet Oncol 20:674–685 https://doi.org/10.1016/S1470-2045(18)30931-8
113	R Mohan, D Grosshans (2017) Proton therapy: present and future. Adv Drug Deliv Rev 109:26–44 https://doi.org/10.1016/j.addr.2016.11.006
114	S Mumbauer, J Pascual, I Kolotuev, F Hamaratoglu (2019) Ferritin heavy chain protects the developing wing from reactive oxygen species and ferroptosis. PLoS Genet 15: https://doi.org/10.1371/journal.pgen.1008396
115	MA Nehs, C-I Lin, DE Kozono, EE Whang, NL Cho, K Zhu, J Moalem, FD Jr Moore, DT Ruan (2011) Necroptosis is a novel mechanism of radiation-induced cell death in anaplastic thyroid and adrenocortical cancers. Surgery 150:1032–1039 https://doi.org/10.1016/j.surg.2011.09.012
116	HP Nguyen, D Yi, F Lin, JA Viscarra, C Tabuchi, K Ngo, G Shinet al. (2020) Aifm2, a NADH oxidase, supports robust glycolysis and is required for cold-and diet-induced thermogenesis. Mol Cell 77 (600–617): https://doi.org/10.1016/j.molcel.2019.12.002
117	Y Ohiro, I Garkavtsev, S Kobayashi, KR Sreekumar, R Nantz, BT Higashikubo, SL Duffy, R Higashikubo, A Usheva, D Gius (2002) A novel p53-inducible apoptogenic gene, PRG3, encodes a homologue of the apoptosis-inducing factor (AIF). FEBS Lett 524:163–171 https://doi.org/10.1016/S0014-5793(02)03049-1
118	Y Ou, S-J Wang, D Li, B Chu, W Gu (2016) Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc Natl Acad Sci 113:E6806–E6812 https://doi.org/10.1073/pnas.1607152113
119	MS Padanad, G Konstantinidou, N Venkateswaran, M Melegari, S Rindhe, M Mitsche, C Yang, K Batten, KE Huffman, J Liu (2016) Fatty acid oxidation mediated by Acyl-CoA synthetase long chain 3 is required for mutant KRAS lung tumorigenesis. Cell Rep 16:1614–1628 https://doi.org/10.1016/j.celrep.2016.07.009
120	X Pan, Z Lin, D Jiang, Y Yu, D Yang, H Zhou, D Zhan, S Liu, G Peng, Z Chen (2019) Erastin decreases radioresistance of NSCLC cells partially by inducing GPX4-mediated ferroptosis. Oncol Lett 17:3001–3008 https://doi.org/10.3892/ol.2019.9888
121	M Pang, X Liu, B Slagle-Webb, A Madhankumar, J Connor (2016) Role of h-ferritin in radiosensitivity of human gliomacells. J Cancer Biol Treat 3:1–10 https://doi.org/10.24966/CBT-7546/100006
122	R Pathak, SA Pawar, Q Fu, PK Gupta, M Berbée, S Garg, V Sridharan, W Wang, PG Biju, KJ Krager (2014) Characterization of transgenic Gfrp knock-in mice: implications for tetrahydrobiopterin in modulation of normal tissue radiation responses. Antioxid Redox Signal 20:1436–1446 https://doi.org/10.1089/ars.2012.5025
123	CM Paton, JM Ntambi (2009) Biochemical and physiological function of stearoyl-CoA desaturase. Am J Physiol Endocrinol Metab 297: E28–E37 https://doi.org/10.1152/ajpendo.90897.2008
124	Q Ran, H Liang, Y Ikeno, W Qi, TA Prolla, LJ Roberts, N Wolf, H VanRemmen, A Richardson (2007) Reduction in glutathione peroxidase 4 increases life span through increased sensitivity to apoptosis. J Gerontol A 62:932–942 https://doi.org/10.1093/gerona/62.9.932
125	SG Rao, JG Jackson (2016) SASP: tumor suppressor or promoter? Yes! Trends Cancer 2:676–687 https://doi.org/10.1016/j.trecan.2016.10.001
126	JA Reisz, N Bansal, J Qian, W Zhao, CM Furdui (2014) Effects of ionizing radiation on biological molecules—mechanisms of damage and emerging methods of detection. Antioxid Redox Signal 21:260–292 https://doi.org/10.1089/ars.2013.5489
127	RJ Sabin, RM Anderson (2011) Cellular Senescence-its role in cancer and the response to ionizing radiation. Genome Integrity 2:7 https://doi.org/10.1186/2041-9414-2-7
128	T Sanli, A Rashid, C Liu, S Harding, RG Bristow, J-C Cutz, G Singh, J Wright, T Tsakiridis (2010) Ionizing radiation activates AMPactivated kinase (AMPK): a target for radiosensitization of human cancer cells. Int J Radiat Oncol Biol Phys 78:221–229 https://doi.org/10.1016/j.ijrobp.2010.03.005
129	T Sanli, GR Steinberg, G Singh, T Tsakiridis (2014) AMP-activated protein kinase (AMPK) beyond metabolism: a novel genomic stress sensor participating in the DNA damage response pathway. Cancer Biol Ther 15:156–169 https://doi.org/10.4161/cbt.26726
130	H Sato, M Tamba, T Ishii, S Bannai (1999) Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J Biol Chem 274:11455–11458 https://doi.org/10.1074/jbc.274.17.11455
131	H Sato, A Shiiya, M Kimata, K Maebara, M Tamba, Y Sakakura, N Makino, F Sugiyama, K-I Yagami, T Moriguchi (2005) Redox imbalance in cystine/glutamate transporter-deficient mice. J Biol Chem 280:37423–37429 https://doi.org/10.1074/jbc.M506439200
132	O Shadyro, I Yurkova, M Kisel (2002) Radiation-induced peroxidation and fragmentation of lipids in a model membrane. Int J Radiat Biol 78:211–217 https://doi.org/10.1080/09553000110104065
133	R Shah, MS Shchepinov, DA Pratt (2018) Resolving the role of lipoxygenases in the initiation and execution of ferroptosis. ACS Central Sci 4:387–396 https://doi.org/10.1021/acscentsci.7b00589
134	M Sheikh, AJ Fornace (2000) Death and decoy receptors and p53-mediated apoptosis. Leukemia 14:1509–1513 https://doi.org/10.1038/sj.leu.2401865
135	K Shimada, R Skouta, A Kaplan, WS Yang, M Hayano, SJ Dixon, LM Brown, CA Valenzuela, AJ Wolpaw, BR Stockwell (2016) Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol 12:497–503 https://doi.org/10.1038/nchembio.2079
136	R Singhal, SR Mitta, KP Olive, CA Lyssiotis, YM Shah (2019) Hypoxia inducible factor-2α increases sensitivity of colon cancer cells towards oxidative cell death. BioRxiv, 823997 https://doi.org/10.1101/823997
137	YP Song, RJ Colaco (2018) Radiation necrosis-a growing problem in a case of brain metastases following whole brain radiotherapy and stereotactic radiosurgery. Cureus 10 https://doi.org/10.7759/cureus.2037
138	X Song, S Zhu, P Chen, W Hou, Q Wen, J Liu, Y Xie, J Liu, DJ Klionsky, G Kroemer (2018) AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system Xc-activity. Curr Biol 28(2388–2399): https://doi.org/10.1016/j.cub.2018.05.094
139	M Soula, RA Weber, O Zilka, H Alwaseem, K La, F Yen, H Molina, J Garcia-Bermudez, DA Pratt, K Birsoy (2020) Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat Chem Biol 16:1351–1360 https://doi.org/10.1038/s41589-020-0613-y
140	BR Stockwell, JPF Angeli, H Bayir, AI Bush, M Conrad, SJ Dixon, S Fulda, S Gascón, SK Hatzios, VE Kagan (2017) Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171:273–285 https://doi.org/10.1016/j.cell.2017.09.021
141	BR Stockwell, X Jiang, W Gu (2020) Emerging mechanisms and disease relevance of ferroptosis. Trends Cell Biol https://doi.org/10.1016/j.tcb.2020.02.009
142	X Sun, X Niu, R Chen, W He, D Chen, R Kang, D Tang (2016) Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology 64:488–500 https://doi.org/10.1002/hep.28574
143	S Suzuki, T Tanaka, MV Poyurovsky, H Nagano, T Mayama, S Ohkubo, M Lokshin, H Hosokawa, T Nakayama, Y Suzuki (2010) Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci 107:7461–7466 https://doi.org/10.1073/pnas.1002459107
144	A Tarangelo, L Magtanong, KT Bieging-Rolett, Y Li, J Ye, LD Attardi, SJ Dixon (2018) p53 suppresses metabolic stress-induced ferroptosis in cancer cells. Cell Rep 22:569–575 https://doi.org/10.1016/j.celrep.2017.12.077
145	L Tesfay, BT Paul, A Konstorum, Z Deng, AO Cox, J Lee, CM Furdui, P Hegde, FM Torti, SV Torti (2019) Stearoyl-coa desaturase 1protects ovarian cancer cells from ferroptotic cell death. Cancer Res 79:5355–5366 https://doi.org/10.1158/0008-5472.CAN-19-0369
146	J Thariat, J-M Hannoun-Levi, AS Myint, T Vuong, J-P Gérard (2013) Past, present, and future of radiotherapy for the benefit of patients. Nat Rev Clin Oncol 10:52 https://doi.org/10.1038/nrclinonc.2012.203
147	J Tsoi, L Robert, K Paraiso, C Galvan, KM Sheu, J Lay, DJ Wong, M Atefi, R Shirazi, X Wang (2018) Multi-stage differentiation defines melanoma subtypes with differential vulnerability to druginduced iron-dependent oxidative stress. Cancer Cell 33(890–904): https://doi.org/10.1016/j.ccell.2018.03.017
148	H Vakifahmetoglu, M Olsson, B Zhivotovsky (2008) Death through a tragedy: mitotic catastrophe. Cell Death Differ 15:1153–1162 https://doi.org/10.1038/cdd.2008.47
149	M Vařecha, J Amrichová, M Zimmermann, V Ulman, E Lukášová, M Kozubek (2007) Bioinformatic and image analyses of the cellular localization of the apoptotic proteins endonuclease G, AIF, and AMID during apoptosis in human cells. Apoptosis 12:1155–1171 https://doi.org/10.1007/s10495-007-0061-0
150	D Venkatesh, NA O’Brien, F Zandkarimi, DR Tong, ME Stokes, DE Dunn, ES Kengmana, AT Aron, AM Klein, JM Csuka (2020) MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling. Genes Dev 34:526–543 https://doi.org/10.1101/gad.334219.119
151	VS Viswanathan, MJ Ryan, HD Dhruv, S Gill, OM Eichhoff, B Seashore-Ludlow, SD Kaffenberger, JK Eaton, K Shimada, AJ Aguirre (2017) Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547:453–457 https://doi.org/10.1038/nature23007
152	KH Vousden (2000) p53: death star. Cell 103:691–694 https://doi.org/10.1016/S0092-8674(00)00171-9
153	T Walden, H Hughes (1988) SpringerLink (Online service). Prostaglandin and lipid metabolism in radiation injury. Springer, Boston https://doi.org/10.1007/978-1-4684-5457-4
154	L Wang, H Cai, Y Hu, F Liu, S Huang, Y Zhou, J Yu, J Xu, F Wu (2018) A pharmacological probe identifies cystathionine β-synthase as a new negative regulator for ferroptosis. Cell Death Dis 9:1–17 https://doi.org/10.1038/s41419-018-1063-2
155	H Wang, H Jiang, M Van De Gucht, M De Ridder (2019a) Hypoxic radioresistance: can ROS be the key to overcome it? Cancers 11:112 https://doi.org/10.3390/cancers11010112
156	W Wang, M Green, JE Choi, M Gijón, PD Kennedy, JK Johnson, P Liao, X Lang, I Kryczek, A Sell (2019b) CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569:270–274 https://doi.org/10.1038/s41586-019-1170-y
157	Y Wang, L Yang, X Zhang, W Cui, Y Liu, QR Sun, Q He, S Zhao, GA Zhang, Y Wang (2019c) Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53. EMBO Rep 20: https://doi.org/10.15252/embr.201847563
158	L Wang, Y Liu, T Du, H Yang, L Lei, M Guo, H-F Ding, J Zhang, H Wang, X Chen (2020) ATF3 promotes erastin-induced ferroptosis by suppressing system Xc–. Cell Death Differ 27:662–675 https://doi.org/10.1038/s41418-019-0380-z
159	SE Wenzel, YY Tyurina, J Zhao, CMS Croix, HH Dar, G Mao, VA Tyurin, TS Anthonymuthu, AA Kapralov, AA Amoscato (2017) PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 171(628–641): https://doi.org/10.1016/j.cell.2017.09.044
160	MV Williams, ND James, E Summers, A Barrett, DV Ash, A Sub-Committee (2006) National survey of radiotherapy fractionation practice in 2003. Clin Oncol 18:3–14 https://doi.org/10.1016/j.clon.2005.10.002
161	HR Withers (1985) Biologic basis for altered fractionation schemes. Cancer 55:2086–2095 https://doi.org/10.1002/1097-0142(19850501)55:9+<2086::AID-CNCR2820551409>3.0.CO;2-1
162	M Wolszczak, J Gajda (2010) Iron release from ferritin induced by light and ionizing radiation. Res Chem Intermed 36:549–563 https://doi.org/10.1007/s11164-010-0155-0
163	JH Woo, Y Shimoni, WS Yang, P Subramaniam, A Iyer, P Nicoletti, MR Martínez, G López, M Mattioli, R Realubit (2015) Elucidating compound mechanism of action by network perturbation analysis. Cell 162:441–451 https://doi.org/10.1016/j.cell.2015.05.056
164	D Wu, C Prives (2018) Relevance of the p53–MDM2 axis to aging. Cell Death Differ 25:169–179 https://doi.org/10.1038/cdd.2017.187
165	M Wu, L-G Xu, X Li, Z Zhai, H-B Shu (2002) AMID, an apoptosisinducing factor-homologous mitochondrion-associated protein, induces caspase-independent apoptosis. J Biol Chem 277:25617–25623 https://doi.org/10.1074/jbc.M202285200
166	M Wu, L-G Xu, T Su, Y Tian, Z Zhai, H-B Shu (2004) AMID is a p53-inducible gene downregulated in tumors. Oncogene 23:6815–6819 https://doi.org/10.1038/sj.onc.1207909
167	L Xie, X Song, J Yu, W Guo, L Wei, Y Liu, X Wang (2011) Solute carrier protein family may involve in radiation-induced radioresistance of non-small cell lung cancer. J Cancer Res Clin Oncol 137:1739 https://doi.org/10.1007/s00432-011-1050-9
168	Y Xie, S Zhu, X Song, X Sun, Y Fan, J Liu, M Zhong, H Yuan, L Zhang, TR Billiar (2017) The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep 20:1692–1704 https://doi.org/10.1016/j.celrep.2017.07.055
169	B Yan, Y Ai, Q Sun, Y Ma, Y Cao, J Wang, Z Zhang, X Wang (2020) Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1. Mol Cell https://doi.org/10.1016/j.molcel.2020.11.024
170	D Yang, T Yaguchi, T Nagata, A Gotoh, S Dovat, C Song, T Nishizaki (2011) AMID mediates adenosine-induced caspase-independent HuH-7 cell apoptosis. Cell Physiol Biochem 27:37–44 https://doi.org/10.1159/000325203
171	WS Yang, R SriRamaratnam, ME Welsch, K Shimada, R Skouta, VS Viswanathan, JH Cheah, PA Clemons, AF Shamji, CB Clish (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156:317–331 https://doi.org/10.1016/j.cell.2013.12.010
172	WS Yang, KJ Kim, MM Gaschler, M Patel, MS Shchepinov, BR Stockwell (2016) Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci 113: E4966–E4975 https://doi.org/10.1073/pnas.1603244113
173	LF Ye, KR Chaudhary, F Zandkarimi, AD Harken, CJ Kinslow, PS Upadhyayula, A Dovas, DM Higgins, H Tan, Y Zhang (2020) Radiation-induced lipid peroxidation triggers ferroptosis and synergizes with ferroptosis inducers. ACS Chem Biol 15:469–484 https://doi.org/10.1021/acschembio.9b00939
174	J Yi, J Zhu, J Wu, CB Thompson, X Jiang (2020) Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis. Proc Natl Acad Sci 117:31189–31197 https://doi.org/10.1073/pnas.2017152117
175	S-E Yoo, L Chen, R Na, Y Liu, C Rios, H Van Remmen, A Richardson, Q Ran (2012) Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain. Free Radical Biol Med 52:1820–1827 https://doi.org/10.1016/j.freeradbiomed.2012.02.043
176	D Zhang, W Wang , X Sun, D Xu, C Wang, Q Zhang, H Wang, W Luo, Y Chen, H Chen (2016) AMPK regulates autophagy by phosphorylating BECN1 at threonine 388. Autophagy 12:1447–1459 https://doi.org/10.1080/15548627.2016.1185576
177	Y Zhang, Y Qian, J Zhang, W Yan, Y-S Jung, M Chen, E Huang, K Lloyd, Y Duan, J Wang (2017) Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2. Genes Dev 31:1243–1256 https://doi.org/10.1101/gad.299388.117
178	Y Zhang, J Shi, X Liu, L Feng, Z Gong, P Koppula, K Sirohi, X Li, Y Wei, H Lee (2018) BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol 20:1181–1192 https://doi.org/10.1038/s41556-018-0178-0
179	Y Zhang, H Tan, JD Daniels, F Zandkarimi, H Liu, LM Brown, K Uchida, OA O’Connor, BR Stockwell (2019a) Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell Chem Biol 26(623–633): https://doi.org/10.1016/j.chembiol.2019.01.008
180	Y Zhang, L Zhuang, B Gan (2019b) BAP1 suppresses tumor development by inducing ferroptosis upon SLC7A11 repression. Mol Cell Oncol 6:1536845 https://doi.org/10.1080/23723556.2018.1536845
181	X Zhang, S Sui, L Wang, H Li, L Zhang, S Xu, X Zheng (2020) Inhibition of tumor propellant glutathione peroxidase 4 induces ferroptosis in cancer cells and enhances anticancer effect of cisplatin. J Cell Physiol 235:3425–3437 https://doi.org/10.1002/jcp.29232
182	J Zheng, M Conrad (2020) The metabolic underpinnings of ferroptosis. Cell Metabol https://doi.org/10.1016/j.cmet.2020.10.011
183	J Zhu, M Berisa, S Schwörer, W Qin, JR Cross, CB Thompson (2019) Transsulfuration activity can support cell growth upon extracellular cysteine limitation. Cell Metab 30(865–876): https://doi.org/10.1016/j.cmet.2019.09.009
184	Y Zong, S Feng, C Yu, J Cheng, G Lu (2017) Up-regulated ATF4 expression increases cell sensitivity to apoptosis in response to radiation. Cell Physiol Biochem 41:784–794 https://doi.org/10.1159/000458742
185	Y Zou, SL Schreiber (2020) Progress in understanding ferroptosis and challenges in its targeting for therapeutic benefit. Cell Chem Biol 27:463–471 https://doi.org/10.1016/j.chembiol.2020.03.015
186	Y Zou, MJ Palte, AA Deik, H Li, JK Eaton, W Wang, Y-Y Tseng, R Deasy, M Kost-Alimova, V Dančík (2019) A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun 10:1–13 https://doi.org/10.1038/s41467-019-09277-9
187	Y Zou, WS Henry, EL Ricq, ET Graham, VV Phadnis, P Maretich, S Paradkar, N Boehnke, AA Deik, F Reinhardt (2020a) Plasticity of ether lipids promotes ferroptosis susceptibility and evasion. Nature 585:603–608 https://doi.org/10.1038/s41586-020-2732-8
188	Y Zou, H Li, ET Graham, AA Deik, JK Eaton, W Wang, G Sandoval-Gomez, CB Clish, JG Doench, SL Schreiber (2020b) Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat Chem Biol 16:302–309 https://doi.org/10.1038/s41589-020-0472-6

[1]	Pranavi Koppula, Li Zhuang, Boyi Gan. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy[J]. Protein Cell, 2021, 12(8): 599-620.
[2]	Abigail Wong-Rolle, Haohan Karen Wei, Chen Zhao, Chengcheng Jin. Unexpected guests in the tumor microenvironment: microbiome in cancer[J]. Protein Cell, 2021, 12(5): 426-435.
[3]	Juanjuan Yuan, Ting Cai, Xiaojun Zheng, Yangzi Ren, Jingwen Qi, Xiaofei Lu, Huihui Chen, Huizhen Lin, Zijie Chen, Mengnan Liu, Shangwen He, Qijun Chen, Siyang Feng, Yingjun Wu, Zhenhai Zhang, Yanqing Ding, Wei Yang. Potentiating CD8⁺ T cell antitumor activity by inhibiting PCSK9 to promote LDLRmediated TCR recycling and signaling[J]. Protein Cell, 2021, 12(4): 240-260.
[4]	Yelei Guo, Kaichao Feng, Yao Wang, Weidong Han. Targeting cancer stem cells by using chimeric antigen receptor-modified T cells: a potential and curable approach for cancer treatment[J]. Protein Cell, 2018, 9(6): 516-526.
[5]	Yanjing Song, Chuan Tong, Yao Wang, Yunhe Gao, Hanren Dai, Yelei Guo, Xudong Zhao, Yi Wang, Zizheng Wang, Weidong Han, Lin Chen. Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo[J]. Protein Cell, 2018, 9(10): 867-878.
[6]	Jiangtao Ren, Yangbing Zhao. Advancing chimeric antigen receptor T cell therapy with CRISPR/Cas9[J]. Protein Cell, 2017, 8(9): 634-643.
[7]	Hua Li, Yangbing Zhao. Increasing the safety and efficacy of chimeric antigen receptor T cell therapy[J]. Protein Cell, 2017, 8(8): 573-589.
[8]	Dongfang Liu, Shuo Tian, Kai Zhang, Wei Xiong, Ndongala Michel Lubaki, Zhiying Chen, Weidong Han. Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV[J]. Protein Cell, 2017, 8(12): 861-877.
[9]	Nicholas Borcherding,David Kusner,Guang-Hui Liu,Weizhou Zhang. ROR1, an embryonic protein with an emerging role in cancer biology[J]. Protein Cell, 2014, 5(7): 496-502.
[10]	Juan Ma,Huamin Han,Li Ma,Changzhen Liu,Xin Xue,Pan Ma,Xiaomei Li,Hua Tao. The immunostimulatory effects of retinoblastoma cell supernatant on dendritic cells[J]. Protein Cell, 2014, 5(4): 307-316.
[11]	Shuanglin Deng,Shan Zhu,Yuan Qiao,Yong-Jun Liu,Wei Chen,Gang Zhao,Jingtao Chen. Recent advances in the role of toll-like receptors and TLR agonists in immunotherapy for human glioma[J]. Protein Cell, 2014, 5(12): 899-911.

Viewed

Full text

Abstract

Cited

Shared

Discussed