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

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.

Automated summary

The interplay between the signals of MTOR and GPX4 modulates autophagy-dependent ferroptosis in human pancreatic cancer cells, with GPX4 playing an essential role in inhibiting this process. Depletion of GPX4 enhances the anticancer activity of rapamycin and RSL3 in vitro or in vivo. These findings may lead to the development of new antitumor therapy targeting autophagy-dependent cell death.