The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression
The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression
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DOI：
10.1038/s41422-019-0263-3
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发表时间：
2020-01-16
期刊：
影响因子：
44.1
通讯作者：
Gan, Boyi
中科院分区：
文献类型：
--
作者：
Lei, Guang;Zhang, Yilei;Gan, Boyi
铁凋亡是一种由脂质过氧化作用引起的调节性细胞死亡，最近被确定为一种天然的肿瘤抑制机制。在这里，我们表明，电离辐射（IR）诱导癌细胞中的铁凋亡。从机制上讲，IR不仅诱导活性氧（ROS），还诱导ACSL 4（一种铁凋亡所需的脂质代谢酶）的表达，导致脂质过氧化和铁凋亡升高。ACSL 4消融在很大程度上消除了IR诱导的铁凋亡，并促进了辐射抗性。IR还诱导包括SLC7A11和GPX4的铁凋亡抑制剂的表达作为适应性反应。IR或KEAP 1缺陷诱导的SLC7A11表达通过抑制铁凋亡促进辐射抗性。用铁凋亡诱导剂（FNs）灭活SLC7A11或GPX4可使放射抗性癌细胞和异种移植肿瘤对IR敏感。此外，放射治疗可诱导癌症患者的铁凋亡，而铁凋亡增加与癌症患者对放射治疗的更好反应和更长生存期相关。我们的研究揭示了以前未被认识到的IR和铁凋亡之间的联系，并表明在癌症治疗中进一步探索放射治疗和FINS的组合是必要的。
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.