Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition

Kevin Bray, Robin Mathew, Alexandria Lau, Jurre J. Kamphorst, Jing Fan, Jim Chen, Hsin Yi Chen, Anahita Ghavami, Mark Stein, Robert S. DiPaola, Donna Zhang, Joshua D. Rabinowitz, Eileen White

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92 Scopus citations

Abstract

mTOR inhibitors are used clinically to treat renal cancer but are not curative. Here we show that autophagy is a resistance mechanism of human renal cell carcinoma (RCC) cell lines to mTOR inhibitors. RCC cell lines have high basal autophagy that is required for survival to mTOR inhibition. In RCC4 cells, inhibition of mTOR with CCI-779 stimulates autophagy and eliminates RIP kinases (RIPKs) and this is blocked by autophagy inhibition, which induces RIPK- and ROS-dependent necroptosis in vitro and suppresses xenograft growth. Autophagy of mitochondria is required for cell survival since mTOR inhibition turns off Nrf2 antioxidant defense. Thus, coordinate mTOR and autophagy inhibition leads to an imbalance between ROS production and defense, causing necroptosis that may enhance cancer treatment efficacy.

Original languageEnglish (US)
Article numbere41831
JournalPloS one
Volume7
Issue number7
DOIs
StatePublished - Jul 26 2012

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Bray, K., Mathew, R., Lau, A., Kamphorst, J. J., Fan, J., Chen, J., Chen, H. Y., Ghavami, A., Stein, M., DiPaola, R. S., Zhang, D., Rabinowitz, J. D., & White, E. (2012). Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. PloS one, 7(7), [e41831]. https://doi.org/10.1371/journal.pone.0041831