Regulation of 25-hydroxyvitamin D-1α-hydroxylase by epidermal growth factor in prostate cells

Abstract

Accumulating data suggest that local production of 1α,25-dihydroxyvitamin D (1α,25(OH) 2D) could provide an important cell growth regulatory mechanism in an autocrine fashion in prostate cells. Previously, we demonstrated a differential expression of 1α-OHase enzymatic activity among noncancerous (PZHPV-7) and cancer cells (PC-3, DU145, LNCaP), which appears to correlate with 1α-OHase m-RNA synthesis and its promoter activities. Since it is well-established that EGF regulates the proliferation of prostate cells via autocrine and paracrine loops and 1α,25(OH) 2D inhibites prostate cell proliferation, we investigated if EGF also regulated 1α-OHase expression in prostate cells. We found that EGF upregulated 1α-OHase promoter activity and enzyme activity in PZ-HPV-7 and that 1α,25(OH) 2D 3 inhibited EGF-dependent up-regulation of 1α-OHase enzymatic activity. Moreover, the EGF-stimulated promoter activity was inhibited 70% by the MAPKK inhibitor, PD98059, suggesting that the MAPK pathway may be one pathway involved in the regulation of prostatic 1α-OHase by EGF to increase1α,25(OH) 2D synthesis as a feedback regulator of cell growth. Because EGF has no effect on 1α-OHase promoter activity in LNCaP cells, we propose that the ability of EGF to stimulate 1α,25(OH) 2D synthesis may be abolished or diminished in cancer cells.