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.
authors: The Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.
authors: Kevin
authors: K
authors: Bray
authors: Robin
authors: R
authors: Mathew
authors: Alexandria
authors: A
authors: Lau
authors: Jurre J
authors: JJ
authors: Kamphorst
authors: Jing
authors: J
authors: Fan
authors: Jim
authors: J
authors: Chen
authors: Hsin-Yi
authors: HY
authors: Chen
authors: Anahita
authors: A
authors: Ghavami
authors: Mark
authors: M
authors: Stein
authors: Robert S
authors: RS
authors: DiPaola
authors: Donna
authors: D
authors: Zhang
authors: Joshua D
authors: JD
authors: Rabinowitz
authors: Eileen
authors: E
authors: White
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D001481:Basal Metabolism / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009336:Necrosis; D010084:Oxidation-Reduction / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D047428:Protein Kinase Inhibitors; D002738:Chloroquine; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases