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

Abstract

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.

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Fig. 1: MTOR inhibitor induces GPX4 protein degradation.
Fig. 2: GPX4 inhibitor induces autophagy.
Fig. 3: GPX4 depletion induces autophagy-dependent ferroptosis.
Fig. 4: Rapamycin induces autophagy-dependent ferroptosis in vivo.
Fig. 5: GPX4 depletion in PDAC cells enhances anticancer activity of rapamycin in vivo.

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Acknowledgements

We thank Dave Primm (Department of Surgery, University of Texas Southwestern Medical Center) for his critical reading of the paper. J.L. is supported by grants from the National Natural Science Foundation of China (31671435, 81400132, and 81772508).

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Correspondence to Daolin Tang.

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Liu, Y., Wang, Y., Liu, J. et al. Interplay between MTOR and GPX4 signaling modulates autophagy-dependent ferroptotic cancer cell death. Cancer Gene Ther (2020). https://doi.org/10.1038/s41417-020-0182-y

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