1,25 dihydroxyvitamin D regulation of energy metabolism in MCF10 human breast epithelial cells

Abstract

These studies were designed to investigate the impact of 1,25 dihydroxyvitamin D (1,25D) on the metabolic reprogramming during cancer progression towards increased glycolysis and lactate production, and reduced oxidative metabolism (Warburg effect). The ras‐oncogene transfected MCF10 human breast epithelial cells were used to study early breast cancer progression. Metabolite fluxes at the cell membrane were measured by a selective micro biosensor (mFlux), [13C6]glucose flux by 13C‐mass isotopomer distribution analysis of media metabolites (gFlux), and intracellular metabolite levels by NMR following four day 1,25D treatment. Flux of glucose to 3‐phosphoglycerate (gFlux) was reduced 32% by 1,25D, supporting a reduction in glycolysis by 1,25D. 1,25D‐induced reduction in the citric acid (TCA) cycle activity was supported by a 41% reduced flux of glucose to acetyl‐coA (gFlux), a 20% reduced oxygen uptake (mFlux) and a 29% reduced intracellular succinate (NMR). Moreover, 1,25D reduced the flux of glucose to lactate by 10% (gFlux) and reduced intracellular lactate by 55% (NMR), which is consistent with a 15% reduction in lactate dehydrogenase activity, the enzyme converting pyruvate to lactate. These studies suggest 1,25D regulates energy metabolism in early cancer progression, shifting glucose utilization towards reduced glycolysis and lactate production as well as reduced flux through the TCA cycle.Grant Funding Source : NIH R25CA128770