Effect of 1,25 dihydroxyvitamin D on energy metabolism in MCF10A breast epithelial cells

Abstract

These studies were designed to investigate the impact of 1,25 dihydroxyvitamin D (1,25D) on the critical shift to cancer progression. This shift is mediated by hypoxia inducible factor-1α (HIF-1α), to alter energy metabolism towards increased glycolysis, reduced oxidative metabolism and increased lactate production (Warburg effect). Our results show that 1,25D reduces HIF-1α protein level by 17% (P=0.05) and lactate dehydrogenase activity by 11% (P=0.06) in untransformed (Unt) and ras-oncogene transfected (ras) MCF10A breast epithelial cells. A highly sensitive micro biosensor in self-referencing mode was used to measure physiological glucose, oxygen and lactate flux at the cell membrane. Glucose and oxygen flux was higher in ras cells (328±17 and 2123±22 pmol/cm2/sec, respectively) than Unt cells (156±19 and 967±21 pmol/cm2/sec, respectively, P<0.01), characteristic of Warburg effect. Long term (4 days) 1,25D treatment induces glucose (16%) and oxygen uptake (19%) in response to additional glucose (10 μM) in ras cells compared to vehicle treated cells. However, with increasing doses of glucose, lactate efflux was similar between vehicle and 1,25D treated ras cells. These studies suggest that 1,25D may shift glucose utilization towards increased glucose and oxygen uptake, but not lactate production, thus may regulate energy metabolism in cancer progression. Grant Funding Source: R25CA128770/CA/NCI NIH