title: Carnitine palmitoyltransferase 1A functions to repress FoxO transcription factors to allow cell cycle progression in ovarian cancer.
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.
authors.affiliation: Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.|Institute of Biological Sciences, Shaanxi Normal University, Xi'an, China.
authors.forename: Huanjie
authors.initials: H
authors.lastname: Shao
authors.affiliation: Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Esraa M
authors.initials: EM
authors.lastname: Mohamed
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Guoyan G
authors.initials: GG
authors.lastname: Xu
authors.affiliation: Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Waters
authors.affiliation: Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Jing
authors.affiliation: Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Yibao
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
authors.affiliation: Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Idowu
authors.affiliation: Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Fang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D024202:Electrophoretic Mobility Shift Assay; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050356:Lipid Metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; D005227:Fatty Acids; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D000255:Adenosine Triphosphate; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase; D020928:Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases
keywords: CPT1A; FoxO; fatty acid β-oxidation; ovarian cancer; p21