Autophagy Suppresses RIP Kinase-Dependent Necrosis Enabling Survival to mTOR Inhibition

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

来源：PLos One, 2012, 7(7): e41831.

DOI：10.1371/journal.pone.0041831

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.

• 出版日期2012-7-26