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

Bray, K. et al. (2012) Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. PLoS ONE, 7(7), e41831. (doi:10.1371/journal.pone.0041831) (PMID:22848625) (PMCID:PMC3406086)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kamphorst, Dr Jurre
Authors: 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., and White, E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN:1932-6203
ISSN (Online):1932-6203
Copyright Holders:Copyright © 2012 The Authors
First Published:First published in PLoS ONE 7(7):e41831
Publisher Policy:Reproduced under a Creative Commons License

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