1,25 Dihydroxyvitamin D inhibits glutamine metabolism in ras‐transformed MCF10A breast epithelial cells (644.12)

Abstract

Studies were designed to investigate the effect of 1,25 dihydroxyvitamin D (1,25D) on glutamine metabolism during cancer progression employing untransformed (10A) and ras oncogene transformed MCF10A human breast epithelial cells (ras). Glutamine restriction reduced cell number in both cell lines, and 1,25D ameliorated these reductions. Intracellular glutamine and glutamate levels, determined by NMR, were increased 25% in ras cells compared to 10A cells, and 1,25D reduced these levels by 23% in ras cells. Fractional glutamine and glutamate flux, utilizing U13C5‐L‐glutamine, into the TCA cycle was increased in ras cells by 21% and 18%, respectively, compared to 10A cells. 1,25D decreased glutamine flux into the TCA cycle by 18% and 31% in 10A and ras cells, respectively, and decreased glutamate flux into the TCA cycle by 13% and 17% in 10A and ras cells, respectively. The mRNA expression of the glutamine transporter, solute linked carrier family 1 member A5 (SLC1A5), was decreased by 34% in ras compared to 10A cells. 1,25D further decreased SLC1A5 mRNA expression in ras by 45%, but had no effect in 10A cells. These results suggest 1,25D may alter glutamine metabolism in ras cells by inhibiting glutamine uptake and utilization, in part through down‐regulation of SLC1A5. Grant Funding Source: Supported by NIH R25CA128770 and NCI CCSG CA23168