Abstract
Cancer cells rely on hyperactive de novo lipid synthesis for maintaining malignancy. Recent studies suggest involvement in cancer of fatty acid oxidation, a process functionally opposite to lipogenesis. A mechanistic link from lipid catabolism to oncogenic processes is yet to be established. Carnitine palmitoyltransferase 1 (CPT1) is a rate-limiting enzyme of fatty acid β-oxidation (FAO) that catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine, thereby shuttling fatty acids into the mitochondrial matrix for β-oxidation. In the present study, we demonstrated that CPT1A was highly expressed in most ovarian cancer cell lines and primary ovarian serous carcinomas. Overexpression of CPT1A correlated with a poor overall survival of ovarian cancer patients. Inactivation of CPT1A decreased cellular ATP levels and induced cell cycle arrest at G0/G1, suggesting that ovarian cancer cells depend on or are addicted to CPT1A-mediated FAO for cell cycle progression. CPT1A deficiency also suppressed anchorage-independent growth and formation of xenografts from ovarian cancer cell lines. The cyclin-dependent kinase inhibitor p21WAF1 (p21) was identified as most consistently and robustly induced cell cycle regulator upon inactivation of CPT1A. Furthermore, p21 was transcriptionally upregulated by the FoxO transcription factors, which were in turn phosphorylated and activated by AMP-activated protein kinase and the mitogen-activated protein kinases JNK and p38. Our results established the oncogenic relevance of CPT1A and a mechanistic link from lipid catabolism to cell cycle regulation, suggesting that CPT1A could be a prognostic biomarker and rational target for therapeutic intervention of cancer.
Highlights
One of the most fundamental changes in cancer is the development of a lipogenic phenotype, mediated by increased expression or activity of key lipogenic enzymes primarily fatty acid synthase (FAS) and acetylCoA carboxylase (ACC) [1, 2]
We investigated the biological relevance of fatty acid β-oxidation (FAO) to ovarian cancer
Our results www.impactjournals.com/oncotarget indicated that CPT1A, the rate-setting enzyme of FAO is abundantly expressed in a high percentage of ovarian serous carcinomas and ovarian cancer cell lines
Summary
One of the most fundamental changes in cancer is the development of a lipogenic phenotype, mediated by increased expression or activity of key lipogenic enzymes primarily fatty acid synthase (FAS) and acetylCoA carboxylase (ACC) [1, 2]. Recent evidence suggests that fatty acids from neighboring adipose tissues, lipoproteins, membrane phospholipids, and intracellular storage fat have potential to fuel cancer cells [5,6,7,8,9]. Unlike glycolytic www.impactjournals.com/oncotarget and lipogenic pathways where specific metabolic enzymes such as hexokinase 2 and FAS are known to be deregulated by oncogene (s) or by inactivation of tumor suppressors [10, 11], there is limited evidence for cancer-associated abnormal expression or activity of the enzymes directly involved in the FAO pathway. Carnitine palmitoyltransferase 1 (CPT1) is a rate-limiting enzyme of FAO that catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine, thereby shuttling long-chain fatty acids into the mitochondrial matrix [12]. A physiological role for CPT1C in fatty acid metabolism remains controversial [18, 19]
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