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 AMPKa. 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.

Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model

“…Using transient knockdown models for Cpt1c, we reported that Cpt1c promotes tumor growth in response to metabolic stress. 7 These results suggest that cells can use a novel mechanism involving CPT1C to protect against metabolic stress. …”

Fighting Fire with Fire in Cancer

“…Our group has discovered that carnitine palmitoyltransferase-1C (CPT1C), a brainspecific metabolic enzyme, may be involved in tumor cell metabolic adaptation to heightened environmental stress [28]. Expression of CPT1C, but not the ubiquitous CPT1A or heart-specific CPT1B, correlated inversely with mTOR pathway activation in tumor cells, indicating that CPT1C may act in a pathway parallel to mTORenhanced glycolysis [28,29].…”

“…Expression of CPT1C, but not the ubiquitous CPT1A or heart-specific CPT1B, correlated inversely with mTOR pathway activation in tumor cells, indicating that CPT1C may act in a pathway parallel to mTORenhanced glycolysis [28,29]. CPT1C contributes to rapamycin resistance in murine primary tumors and is overexpressed in human non-small-cell lung carcinomas (NSCLC) [28].…”

“…CPT1C overexpression in a human cancer cell line led to increased fatty acid oxidation and ATP production, and resistance to glucose deprivation or hypoxia [28]. Importantly, siRNA-mediated depletion of CPT1C reduced tumor growth in an in vivo xenograft mouse model [28], and delayed tumor development and increased mouse survival in a neurofibromatosis type I tumor model [30][31][32]. Subsequent studies have established that CPT1C is a p53 target gene, and that CPT1C expression is induced by metabolic stress factors such as hypoxia and glucose deprivation in a p53-and AMPK-dependent manner [32].…”

“…CPT1C contributes to rapamycin resistance in murine primary tumors and is overexpressed in human non-small-cell lung carcinomas (NSCLC) [28]. CPT1C overexpression in a human cancer cell line led to increased fatty acid oxidation and ATP production, and resistance to glucose deprivation or hypoxia [28]. Importantly, siRNA-mediated depletion of CPT1C reduced tumor growth in an in vivo xenograft mouse model [28], and delayed tumor development and increased mouse survival in a neurofibromatosis type I tumor model [30][31][32].…”