期刊
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
卷 163, 期 -, 页码 147-156出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2016.04.022
关键词
1,25-Dihydroxyvitamin D; Harvey-ras oncogene; Breast cancer; Prevention; Glutamine metabolism; Energy metabolism
资金
- National Institutes of Health, National Cancer Institute [R25CA128770]
- National Institute for General Medicine [R01GM085291]
- Purdue University Center for Cancer Research Small Grants Program
- Indiana Elks Charities
Breast cancer is the second most common cancer among women in the US. The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)(2)D), is proposed to inhibit cellular processes and to prevent breast cancer. The current studies investigated the effect of 1,25(OH)(2)D on glutamine metabolism during cancer progression employing Harvey-ras oncogene transformed MCF10A human breast epithelial cells (MCF10A-ras). Treatment with 1,25(OH)(2)D significantly reduced intracellular glutamine and glutamate levels measured by nuclear magnetic resonance (NMR) by 23 +/- 2% each. Further, 1,25(OH)(2)D treatment reduced glutamine and glutamate flux, determined by [U-C-13(5)] glutamine tracer kinetics, into the TCA cycle by 31 +/- 0.2% and 17 +/- 0.4%, respectively. The relative levels of mRNA and protein abundance of the major glutamine transporter, solute linked carrier family 1 member A5 (SLC1A5), was significantly decreased by 1,25(OH)(2)D treatment in both MCF10A-ras cells and MCF10A which overexpress ErbB2 (HER-2/neu). Consistent with these results, glutamine uptake was reduced by 1,25(OH)(2)D treatment and the impact was eliminated with the SLC1A5 inhibitor L-gamma-Glutamyl-p-nitroanilide (GPNA). A consensus sequence to the vitamin D responsive element (VDRE) was identified in silico in the SLC1A5 gene promoter, and site-directed mutagenesis analyses with reporter gene studies demonstrate a functional negative VDRE in the promoter of the SLC1A5 gene. siRNA-SLC1A5 transfection in MCF10A-ras cells significantly reduced SLC1A5 mRNA expression as well as decreased viable cell number similar to 1,25 (OH)(2)D treatment. SLC1A5 knockdown also induced an increase in apoptotic cells in MCF10A-ras cells. These results suggest 1,25(OH)(2)D alters glutamine metabolism in MCF10A-ras cells by inhibiting glutamine uptake and utilization, in part through down-regulation of SLC1A5 transcript abundance. Thus, 1,25(OH)(2)D down-regulation of the glutamine transporter, SLC1A5, may facilitate vitamin D prevention of breast cancer. (C) 2016 Elsevier Ltd. All rights reserved.
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