The Third Affiliated Hospital, Guangzhou Medical University, 510510, Guangzhou, Guangdong, China.
Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
Cancer Gene Ther. 2021 Feb;28(1-2):55-63. doi: 10.1038/s41417-020-0182-y. Epub 2020 May 27.
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.
铁死亡近年来成为研究热点，其在癌症治疗中可能具有治疗意义。虽然过度自噬可能导致铁死亡，但其中的潜在分子机制仍知之甚少。本研究提供了新的证据，表明雷帕霉素靶蛋白激酶（MTOR）和谷胱甘肽过氧化物酶 4（GPX4）信号的相互作用调节人胰腺癌细胞中依赖自噬的铁死亡。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 MTOR 激活，并导致人胰腺癌细胞中 GPX4 蛋白降解。此外，GPX4 在雷帕霉素和 RSL3 诱导的依赖自噬的铁死亡抑制中发挥重要作用。因此，RNAi 敲低 GPX4 可增强雷帕霉素和 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应激反应的理解，而且可能为开发针对依赖自噬的细胞死亡的新抗肿瘤治疗方法提供了可能性。
