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

doi:10.1371/journal.pone.0041831

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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129 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 language	English (US)
Article number	e41831
Journal	PloS one
Volume	7
Issue number	7
DOIs	https://doi.org/10.1371/journal.pone.0041831
State	Published - Jul 26 2012

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences
General

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title = "Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition",

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.",

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

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T1 - Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition

AU - Bray, Kevin

AU - Mathew, Robin

AU - Lau, Alexandria

AU - Kamphorst, Jurre J.

AU - Fan, Jing

AU - Chen, Jim

AU - Chen, Hsin Yi

AU - Ghavami, Anahita

AU - Stein, Mark

AU - DiPaola, Robert S.

AU - Zhang, Donna

AU - Rabinowitz, Joshua D.

AU - White, Eileen

PY - 2012/7/26

Y1 - 2012/7/26

N2 - 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.

AB - 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.

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JO - PloS one

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

Abstract

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