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
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