1α, 25-Dihydroxyvitamin D regulates hypoxia-inducible factor-1α in untransformed and Harvey- ras transfected breast epithelial cells

Abstract

The purpose of this study was to determine the mechanism by which 1α, 25-dihydroxyvitamin D (1,25(OH) 2D) alters hypoxia-inducible factor-1α (HIF-1α) protein in untransformed and Harvey- ras (H- ras) oncogene transfected MCF10A breast epithelial cells. Treatment with 1,25(OH) 2D (10 nM) increased both mRNA (2.55 ± 0.6-fold vs. vehicle, p = 0.03) and protein levels (2.37 ± 0.3-fold vs. vehicle, p < 0.0001) of HIF-1α in MCF10A cells in 12 h, which remained elevated at 24 h. However, in H- ras transfected MCF10A cells, 1,25(OH) 2D treatment increased HIF-1α protein level (2.08 ± 0.38-fold vs. vehicle, p = 0.05) at 12 h, with no change in mRNA level and HIF-1α protein level returned to baseline after 24 h. A transcription inhibitor prevented the 1,25(OH) 2D induction of HIF-1α protein and mRNA levels in MCF10A cells, but failed to alter the induction of HIF-1α protein level in H- ras transfected MCF10A cells. On the other hand, inhibition of proteasomal degradation prevented the 1,25(OH) 2D-induced HIF-1α protein level in H- ras transfected MCF10A but not in MCF10A cells. These results support that 1,25(OH) 2D regulates HIF-1α protein level via transcriptional regulation in MCF10A cells in contrast to through proteosomal degradation with the presence of H- ras oncogene in MCF10A cells.