Ferroptosis as a mechanism to mediate p53 function in tumor radiosensitivity.
Ferroptosis as a mechanism to mediate p53 function in tumor radiosensitivity.
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DOI：
10.1038/s41388-021-01790-w
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发表时间：
2021-05
期刊：
影响因子：
8
通讯作者：
Gan B
中科院分区：
文献类型：
--
作者：
Lei G;Zhang Y;Hong T;Zhang X;Liu X;Mao C;Yan Y;Koppula P;Cheng W;Sood AK;Liu J;Gan B
铁下垂是一种由脂质过氧化引发的调节性细胞死亡，最近被认为是放射治疗(RT)介导的肿瘤抑制和放射抵抗的重要机制，尽管在RT中靶向铁下垂的确切遗传背景仍未确定。P53是人类癌症中最常见的突变基因，也是RT的主要效应基因。在这里，我们认为铁下垂是调节肿瘤放射敏感性中P53功能的关键机制。机制上，RT介导的P53激活拮抗RT诱导的SLC7A11的表达，抑制谷胱甘肽的合成，从而促进RT诱导的脂质过氧化和铁下垂。P53缺失至少部分通过SLC7A11介导的铁下垂抑制促进癌细胞或肿瘤的放射抗性。抑制SLC7A11的铁下垂诱导剂(FINS)对肿瘤器官和p53突变或缺失的患者来源的异种移植瘤具有显著的放射增敏作用。最后，我们发现RT诱导的下垂与P53的激活和癌症患者RT的更好的临床结果相关。总之，我们的研究揭示了铁下垂在p53介导的放射增敏中以前未被认识到的作用，并建议联合使用FINS和RT来治疗p53突变的癌症。
Ferroptosis, a form of regulated cell death triggered by lipid peroxidation, was recently identified as an important mechanism in radiotherapy (RT)-mediated tumor suppression and radioresistance, although the exact genetic contexts in which to target ferroptosis in RT remains to be defined. p53 is the most commonly mutated gene in human cancers and a major effector to RT. Here, we identify ferroptosis as a critical mechanism to mediate p53 function in tumor radiosensitivity. Mechanistically, RT-mediated p53 activation antagonizes RT-induced SLC7A11 expression and represses glutathione synthesis, thereby promoting RT-induced lipid peroxidation and ferroptosis. p53 deficiency promotes radioresistance in cancer cells or tumors at least partly through SLC7A11-mediated ferroptosis inhibition. Ferroptosis inducers (FINs) that inhibit SLC7A11 exert significant radiosensitizing effects in tumor organoids and patient-derived xenografts with p53 mutation or deficiency. Finally, we show that RT-induced ferroptosis correlates with p53 activation and better clinical outcomes to RT in cancer patients. Together, our study uncovers a previously unappreciated role of ferroptosis in p53-mediated radiosensitization and suggest using FINs in combination with RT to treat p53-mutant cancers.
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影响因子：
6.2
作者：
Delaney, G;Jacob, S;Barton, M
通讯作者：
Barton, M
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
9.7
作者：
Azzam EI;Jay-Gerin JP;Pain D
通讯作者：
Pain D
DOI：
10.1073/pnas.90.12.5742
发表时间：
1993-06-15
影响因子：
11.1
作者：
LEE, JM;BERNSTEIN, A
通讯作者：
BERNSTEIN, A
影响因子：
82.9
作者：
Kopper, Oded;de Witte, Chris J.;Clevers, Hans
通讯作者：
Clevers, Hans