Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-49699
Zaugg, K; Yao, Y; Reilly, P T; Kannan, K; Kiarash, R; Mason, J; Huang, P; Sawyer, S K; Fuerth, B; Faubert, B; Kalliomäki, T; Elia, A J; Luo, X; Nadeem, V; Bungard, D; Yalavarthi, S; Growney, J D; Wakeham, A; Moolani, Y; Silvester, J; Ten, A Y; Bakker, W; Tsuchihara, K; Berger, S L; Hill, R P; Jones, R G; Tsao, M; Robinson, M O; Thompson, C B; Pan, G; Mak, T W (2011). Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes and Development, 25(10):1041-1051.
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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.
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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Clinic for Radiation Oncology|
|DDC:||610 Medicine & health|
|Deposited On:||19 Sep 2011 11:20|
|Last Modified:||28 Nov 2013 00:55|
|Publisher:||Cold Spring Harbor Laboratory Press|
|Additional Information:||Copyright © 2011 by Cold Spring Harbor Laboratory Press|
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