Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress.

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.

• Authors: Kathrin Zaugg, Yi Yao, Patrick T Reilly, Karuppiah Kannan, Reza Kiarash, Jacqueline Mason, Ping Huang, Suzanne K Sawyer, Benjamin Fuerth, Brandon Faubert, Tuula Kalliomäki, Andrew Elia, Xunyi Luo, Vincent Nadeem, David Bungard, Sireesha Yalavarthi, Joseph D Growney, Andrew Wakeham, Yasmin Moolani, Jennifer Silvester, Annick You Ten, Walbert Bakker, Katsuya Tsuchihara, Shelley L Berger, Richard P Hill, Russell G Jones, Ming Tsao, Murray O Robinson, Craig B Thompson, Guohua Pan, Tak W Mak
• Journal: Genes & development (Genes Dev) Vol. 25 Issue 10 Pg. 1041-51 (May 15 2011) ISSN: 1549-5477 [Electronic] United States
• PMID: 21576264 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• Adenosine Triphosphate
• Carnitine O-Palmitoyltransferase
• TOR Serine-Threonine Kinases
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Adenosine Triphosphate (metabolism)
• Animals
• Apoptosis (physiology)
• Carnitine O-Palmitoyltransferase (deficiency, genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival (genetics)
• Cells, Cultured
• Drug Resistance, Neoplasm (genetics)
• Embryonic Stem Cells (enzymology)
• Gene Expression Regulation, Neoplastic
• HCT116 Cells
• Humans
• Hypoxia (pathology)
• Lung Neoplasms (enzymology, pathology)
• Mice
• RNA, Messenger (metabolism)
• Reproducibility of Results
• Stress, Physiological (genetics, physiology)
• TOR Serine-Threonine Kinases (metabolism)
• Transplantation, Heterologous
• Up-Regulation