1α,25-dihydroxyvitamin D inhibits de novo fatty acid synthesis and lipid accumulation in metastatic breast cancer cells through down-regulation of pyruvate carboxylase

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• 作者：Tomasz Wilmanski ; Kimberly Buhman ; Shawn S. Donkin ; John R. Burgess ; Dorothy Teegarden ; ^{teegarden@purdue.edu}
• 关键词：25-hydroxyvitamin D ; 25(OH)D ; 1α ; 25-dihydroxyvitamin D ; 1 ; 25(OH)₂D ; PC ; pyruvate carboxylase ; FA ; fatty acid ; FASN ; fatty acid synthase ; ACC ; acetyl-CoA carboxylase
• 刊名：The Journal of Nutritional Biochemistry
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：40
• 期：Complete
• 页码：194-200
• 全文大小：512 K
• 卷排序：40

文摘

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.