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1α,25‐Dihydroxyvitamin D 3 Inhibits De Novo Fatty Acid Synthesis and Metastatic Capability of Breast Cancer Cells
Author(s) -
Wilmanski Tomasz,
Barnard Alle,
Donkin Shawn,
Parikh Mukti,
Buhman Kimberly,
Kirshner Julia,
Burgess John,
Teegarden Dorothy
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.688.4
Subject(s) - breast cancer , metastatic breast cancer , lipid metabolism , metastasis , fatty acid synthase , fatty acid synthesis , cancer research , acetyl coa carboxylase , cancer , cancer cell , medicine , fatty acid , endocrinology , chemistry , pyruvate carboxylase , biochemistry , enzyme
Breast cancer continues to be the second most commonly diagnosed cancer in American women. Although treatment of localized breast cancer has been effective with five year survival reaching 99%, survival rates drastically decrease to 24% once the tumor has metastasized to distant secondary sites. The most common site of breast cancer metastasis is bone and both higher intracellular lipid accumulation and upregulated de novo fatty acid synthesis correlate with greater breast cell metastatic capability. Therefore, strategies targeting breast cancer cell lipid metabolism may be successful in inhibiting breast to bone metastasis. Here, we demonstrate that the active vitamin D metabolite, 1α,25‐dihydroxyvitamin D (1,25(OH) 2 D), inhibits the metastatic capability of MCF10CA1a (30% of vehicle) and MDA‐MB‐231 breast epithelial cells (80% of vehicle) in an in vitro 3D (rMET) model of breast to bone metastasis. In addition, we show that 1,25(OH) 2 D regulates breast cancer cell lipid metabolism by inhibiting de novo fatty acid synthesis from 13 C[U]‐Glucose (48%±5.5 relative to vehicle) and decreasing neutral lipid accumulation (BODIPY staining) (56%±7.4 relative to vehicle) at 5 days of treatment. In our studies investigating the mechanisms of 1,25(OH) 2 D mediated regulation of lipid metabolism, we identified the mitochondrial enzyme pyruvate carboxylase (PC) as a primary target of 1,25(OH) 2 D. Treatment with 1,25(OH) 2 D decreased both PC mRNA (58%±7 relative to vehicle) and protein (54%±12 relative to vehicle) expression at 5 days. Consistent with these results, de novo fatty acid synthesis from acetate, the immediate substrate for fatty acid synthesis downstream of glucose, was not changed with 1,25(OH) 2 D, supporting a role of PC in 1,25(OH) 2 D mediated inhibition of fatty acid synthesis upstream of lipogenic enzymes. Thus, our studies demonstrate that 1,25(OH) 2 D decreases fatty acid accumulation and metastatic capability, potentially through downregulation of PC. Support or Funding Information This work was supported by a Project Development Team within the ICTSI NIH/NCRR Grant Number UL1TR001108, as well as the National Institutes of Health, National Cancer Institute R25CA128770 (D. Teegarden) Cancer Prevention Internship Program administered by the Oncological Sciences Center and the Discovery Learning Research Center at Purdue University.