文章：

MTOR和GPX4信号之间的相互作用调节自噬依赖性铁嗜癌细胞死亡

Interplay between MTOR and GPX4 signaling modulates autophagy-dependent ferroptotic cancer cell death 

原文发布日期：2020-05-27 

英文摘要：

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. 

摘要翻译： 

铁死亡已成为近年来迅速兴起的研究热点，在癌症治疗领域具有潜在的治疗意义。尽管过度自噬可能促进铁死亡发生，但其潜在分子机制尚不完全明确。本研究提供了新颖证据，表明雷帕霉素激酶机制靶标（MTOR）与谷胱甘肽过氧化物酶4（GPX4）之间的信号交互作用调控人胰腺癌细胞中自噬依赖性铁死亡过程。经典自噬诱导剂雷帕霉素和经典铁死亡激活剂RSL3均可阻断人胰腺癌细胞中MTOR活化并导致GPX4蛋白降解。更重要的是，GPX4在抑制雷帕霉素和RSL3诱导的自噬依赖性铁死亡中起关键作用。因此，通过RNAi技术敲低GPX4表达可增强雷帕霉素和RSL3在体外和体内的抗癌活性。这些发现不仅深化了我们对细胞死亡应激反应的理解，更为靶向自噬依赖性细胞死亡的新型抗肿瘤治疗策略开发提供了可能。

原文链接：

Interplay between MTOR and GPX4 signaling modulates autophagy-dependent ferroptotic cancer cell death