Author:
Zaugg Kathrin,Yao Yi,Reilly Patrick T.,Kannan Karuppiah,Kiarash Reza,Mason Jacqueline,Huang Ping,Sawyer Suzanne K.,Fuerth Benjamin,Faubert Brandon,Kalliomäki Tuula,Elia Andrew,Luo Xunyi,Nadeem Vincent,Bungard David,Yalavarthi Sireesha,Growney Joseph D.,Wakeham Andrew,Moolani Yasmin,Silvester Jennifer,Ten Annick You,Bakker Walbert,Tsuchihara Katsuya,Berger Shelley L.,Hill Richard P.,Jones Russell G.,Tsao Ming,Robinson Murray O.,Thompson Craig B.,Pan Guohua,Mak Tak W.
Abstract
Tumor cells gain a survival/growth advantage by adapting their metabolism to respond to environmental stress, a process known as metabolic transformation. The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells up-regulate glycolysis under aerobic conditions. However, other mechanisms mediating metabolic transformation remain undefined. Here we report that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific metabolic enzyme, may participate in metabolic transformation. CPT1C expression correlates inversely with mammalian target of rapamycin (mTOR) pathway activation, contributes to rapamycin resistance in murine primary tumors, and is frequently up-regulated in human lung tumors. Tumor cells constitutively expressing CPT1C show increased fatty acid (FA) oxidation, ATP production, and resistance to glucose deprivation or hypoxia. Conversely, cancer cells lacking CPT1C produce less ATP and are more sensitive to metabolic stress. CPT1C depletion via siRNA suppresses xenograft tumor growth and metformin responsiveness in vivo. CPT1C can be induced by hypoxia or glucose deprivation and is regulated by AMPKα. Cpt1c-deficient murine embryonic stem (ES) cells show sensitivity to hypoxia and glucose deprivation and altered FA homeostasis. Our results indicate that cells can use a novel mechanism involving CPT1C and FA metabolism to protect against metabolic stress. CPT1C may thus be a new therapeutic target for the treatment of hypoxic tumors.
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
404 articles.
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