Interplay between MTOR and GPX4 signaling modulates autophagy-dependent ferroptotic cancer cell death
Interplay between MTOR and GPX4 signaling modulates autophagy-dependent ferroptotic cancer cell death
复制标题
MTOR 和 GPX4 信号之间的相互作用调节自噬依赖性铁死亡癌细胞死亡
DOI：
10.1038/s41417-020-0182-y
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发表时间：
2020-05-27
影响因子：
6.4
通讯作者：
Tang, Daolin
中科院分区：
文献类型：
--
作者：
Liu, Yang;Wang, Yuan;Tang, Daolin
近年来，铁凋亡已成为一个迅速增长的兴趣，并在癌症治疗中具有可能的治疗意义。虽然过度的自噬可能导致铁凋亡，但其潜在的分子机制仍不清楚。在这里，我们提供了新的证据表明，雷帕霉素激酶（MTOR）和谷胱甘肽过氧化物酶4（GPX4）的机械靶点信号之间的相互作用调节自噬依赖性铁凋亡在人胰腺癌细胞。经典的自噬诱导剂雷帕霉素和经典的铁凋亡激活剂RSL3都可以阻断人胰腺癌细胞中MTOR的激活并导致GPX4蛋白降解。此外，GPX4在抑制由雷帕霉素和RSL3诱导的自噬依赖性铁凋亡中起重要作用。因此，通过RNAi去除GPX 4增强了雷帕霉素和RSL3在体外或体内的抗癌活性。这些发现不仅增加了我们对细胞死亡中应激反应的理解，而且还可能提高开发针对自噬依赖性细胞死亡的新抗肿瘤疗法的可能性。
Ferroptosis has become a topic of rapidly growing interest in recent years, and has possible therapy implications in cancer therapy. Although excessive autophagy may contribute to ferroptosis, its underlying molecular mechanism remains largely unknown. Here, we provide novel evidence that the interplay between the signals of mechanistic target of rapamycin kinase (MTOR) and glutathione peroxidase 4 (GPX4) modulates autophagy-dependent ferroptosis in human pancreatic cancer cells. Both the classical autophagy inducer rapamycin and the classical ferroptosis activator RSL3 can block MTOR activation and cause GPX4 protein degradation in human pancreatic cancer cells. Moreover, GPX4 plays an essential role in the inhibition of autophagy-dependent ferroptosis induced by rapamycin and RSL3. Consequently, GPX4 depletion by RNAi enhances the anticancer activity of rapamycin and RSL3 in vitro or in vivo. These findings not only increase our understanding of stress responses in cell death, but may also raise the possibility of developing new antitumor therapy targeting autophagy-dependent cell death.