The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression

被引:809
|
作者
Lei, Guang [1 ,2 ,3 ,4 ]
Zhang, Yilei [3 ]
Koppula, Pranavi [3 ,5 ]
Liu, Xiaoguang [3 ]
Zhang, Jie [3 ]
Lin, Steven H. [3 ,6 ]
Ajani, Jaffer A. [7 ]
Xiao, Qin [1 ,2 ,4 ]
Liao, Zhongxing [6 ]
Wang, Hui [1 ,2 ,4 ]
Gan, Boyi [3 ,5 ]
机构
[1] Cent S Univ, Hunan Canc Hosp, Dept Radiat Oncol, Changsha 410013, Hunan, Peoples R China
[2] Cent S Univ, Affiliated Canc Hosp, Xiangya Sch Med, Changsha 410013, Hunan, Peoples R China
[3] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA
[4] Key Lab Translat Radiat Oncol, Changsha 410013, Hunan, Peoples R China
[5] Univ Texas MD Anderson Canc Ctr, UTHealth Grad Sch Biomed Sci, Houston, TX 77030 USA
[6] Univ Texas MD Anderson Cenc Ctr, Dept Radiat Oncol, Div Radiat Oncol, Houston, TX 77030 USA
[7] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Div Canc Med, Houston, TX 77030 USA
关键词
OXIDATIVE STRESS; CANCER; SULFASALAZINE; RADIOTHERAPY; PEROXIDATION; TRANSPORTER; HOMEOSTASIS; INHIBITION; CHECKPOINT; ANTIPORTER;
D O I
10.1038/s41422-019-0263-3
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Ferroptosis, a form of regulated cell death caused by lipid peroxidation, was recently identified as a natural tumor suppression mechanism. Here, we show that ionizing radiation (IR) induces ferroptosis in cancer cells. Mechanistically, IR induces not only reactive oxygen species (ROS) but also the expression of ACSL4, a lipid metabolism enzyme required for ferroptosis, resulting in elevated lipid peroxidation and ferroptosis. ACSL4 ablation largely abolishes IR-induced ferroptosis and promotes radioresistance. IR also induces the expression of ferroptosis inhibitors, including SLC7A11 and GPX4, as an adaptive response. IR- or KEAP1 deficiency-induced SLC7A11 expression promotes radioresistance through inhibiting ferroptosis. Inactivating SLC7A11 or GPX4 with ferroptosis inducers (FINs) sensitizes radioresistant cancer cells and xenograft tumors to IR. Furthermore, radiotherapy induces ferroptosis in cancer patients, and increased ferroptosis correlates with better response and longer survival to radiotherapy in cancer patients. Our study reveals a previously unrecognized link between IR and ferroptosis and indicates that further exploration of the combination of radiotherapy and FINs in cancer treatment is warranted.
引用
收藏
页码:146 / 162
页数:17
相关论文
共 50 条
  • [31] Genetic variation in radiation-induced cell death
    Smirnov, Denis A.
    Brady, Lauren
    Halasa, Krzysztof
    Morley, Michael
    Solomon, Sonia
    Cheung, Vivian G.
    GENOME RESEARCH, 2012, 22 (02) : 332 - 339
  • [32] Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases
    Wang, Yingying
    Boerma, Marjan
    Zhou, Daohong
    RADIATION RESEARCH, 2016, 186 (02) : 153 - 161
  • [33] Pharmacologic Profiling of Phosphoinositide 3-Kinase Inhibitors as Mitigators of Ionizing Radiation-Induced Cell Death
    Lazo, John S.
    Sharlow, Elizabeth R.
    Epperly, Michael W.
    Lira, Ana
    Leimgruber, Stephanie
    Skoda, Erin M.
    Wipf, Peter
    Greenberger, Joel S.
    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2013, 347 (03): : 669 - 680
  • [34] Ionizing radiation-induced, Bax-mediated cell death is dependent on activation of cysteine and serine proteases
    Gong, BD
    Chen, Q
    Endlich, B
    Mazumder, S
    Almasan, A
    CELL GROWTH & DIFFERENTIATION, 1999, 10 (07): : 491 - 502
  • [35] Estimation of radiation-induced interphase cell death in cultures of human tumor material and in cell lines
    Marshall, ES
    Baguley, BC
    Matthews, JHL
    Jose, CC
    Furneaux, CE
    Shaw, JHF
    Kirker, JA
    Morton, RP
    White, JB
    Rice, ML
    Isaacs, RJ
    Coutts, R
    Whittaker, JR
    ONCOLOGY RESEARCH, 2004, 14 (06) : 297 - 304
  • [36] Role of inducible heat shock protein 70 in radiation-induced cell death
    Lee, SJ
    Choi, SA
    Lee, KH
    Chung, HY
    Kim, TH
    Cho, CK
    Lee, YS
    CELL STRESS & CHAPERONES, 2001, 6 (03): : 273 - 281
  • [37] Role of cell interactions in initiation of radiation-induced thymocyte death and the problem of apoptosis
    Eidus, LK
    IZVESTIYA AKADEMII NAUK SERIYA BIOLOGICHESKAYA, 1998, (02): : 204 - 212
  • [38] Role of a DNA Damage Checkpoint Pathway in Ionizing Radiation-Induced Glioblastoma Cell Migration and Invasion
    Issai Vanan
    Zhiwan Dong
    Elena Tosti
    Gregg Warshaw
    Marc Symons
    Rosamaria Ruggieri
    Cellular and Molecular Neurobiology, 2012, 32 : 1199 - 1208
  • [39] Role of a DNA Damage Checkpoint Pathway in Ionizing Radiation-Induced Glioblastoma Cell Migration and Invasion
    Vanan, Issai
    Dong, Zhiwan
    Tosti, Elena
    Warshaw, Gregg
    Symons, Marc
    Ruggieri, Rosamaria
    CELLULAR AND MOLECULAR NEUROBIOLOGY, 2012, 32 (07) : 1199 - 1208
  • [40] Ionizing radiation-induced pemphigus foliaceus
    Ambay, A
    Stratman, E
    JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, 2005, 52 (03) : P115 - P115