title: 1α,25-dihydroxyvitamin D inhibits de novo fatty acid synthesis and lipid accumulation in metastatic breast cancer cells through down-regulation of pyruvate carboxylase.
abstract: Both increased de novo fatty acid synthesis and higher neutral lipid accumulation are a common phenotype observed in aggressive breast cancer cells, making lipid metabolism a promising target for breast cancer prevention. In the present studies, we demonstrate a novel effect of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D (1,25(OH)₂D) on lipid metabolism in malignant breast epithelial cells. Treatment of MCF10CA1a breast epithelial cells with 1,25(OH)₂D (10 nM) for 5 and 7 days decreased the level of triacylglycerol, the most abundant form of neutral lipids, by 20%(±3.9) and 50%(±5.9), respectively. In addition, 1,25(OH)₂D treatment for 5 days decreased palmitate synthesis from glucose, the major fatty acid synthesized de novo (48%±5.5 relative to vehicle). We have further identified the anaplerotic enzyme pyruvate carboxylase (PC) as a target of 1,25(OH)₂D-mediated regulation and hypothesized that 1,25(OH)₂D regulates breast cancer cell lipid metabolism through inhibition of PC. PC mRNA expression was down-regulated with 1,25(OH)₂D treatment at 2 (73%±6 relative to vehicle) and 5 (56%±8 relative to vehicle) days. Decrease in mRNA abundance corresponded with a decrease in PC protein expression at 5 days of treatment (54%±12 relative to vehicle). Constitutive overexpression of PC in MCF10CA1a cells using a pCMV6-PC plasmid inhibited the effect of 1,25(OH)₂D on both TAG accumulation and de novo palmitate synthesis from glucose. Together, these studies demonstrate a novel mechanism through which 1,25(OH)₂D regulates lipid metabolism in malignant breast epithelial cells.
authors.affiliation: Department of Nutrition Science, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wilmanski
authors.affiliation: Department of Nutrition Science, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Buhman
authors.affiliation: Department of Nutrition Science, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN.
authors.forename: Shawn S
authors.initials: SS
authors.lastname: Donkin
authors.affiliation: Department of Nutrition Science, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN.
authors.forename: John R
authors.initials: JR
authors.lastname: Burgess
authors.affiliation: Department of Nutrition Science, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN. Electronic address: teegarden@purdue.edu.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Teegarden
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D005227:Fatty Acids / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D011766:Pyruvate Carboxylase / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D005227:Fatty Acids; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; D011766:Pyruvate Carboxylase
keywords: 1α,25-Dihydroxyvitamin D; Breast cancer; Lipid metabolism; Prevention; Pyruvate Carboxylase