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The hormonal form of vitamin D, 1α,25-dihydroxyvitamin D [1α,25(OH)2D] promotes the differentiation and inhibits the proliferation, invasiveness and metastasis of prostate cells. However, 1α,25(OH)2D is not suitable as a chemopreventive agent because its administration can cause hypercalcemia. Serum levels of 1α,25(OH)2D are tightly regulated by the renal enzyme, 25-hydroxyvitamin D-1α-hydroxylase (1α-OHase), which synthesizes 1α,25(OH)2D from the prohormone, 25-hydroxyvitamin D [25(OH)D]. Normal prostate epithelial cells in primary culture, as well as several prostate cancer cell lines, also express 1α-OHase and synthesize the hormone intracellularly. We now investigated the regulation of the prostate 1α-OHase by the three most important regulators of the renal 1α-OHase: calcium, 1α,25(OH)2D and parathyroid hormone (PTH). The 1α-OHase activity in the primary cultures of prostate epithelial cells was inhibited by 1α,25(OH)2D3at 10 and 100 nM, whereas PTH at 10 and 100 nM had no significant effect. Calcium at 1.2 and 2.4 mM had no significant effect on the enzyme activity in the PZ-HPV-7 cell line, a prostate epithelial cell line derived from normal prostate tissue. Conversely, 1.2 or 2.4 mM calcium markedly inhibited 1α-OHase activity in a human kidney cell line used as a positive control. Furthermore, PTH at 100 nM and calcium at 1.2 and 2.4 mM had no effect on the 1α-OHase gene promoter activity in prostate cells, whereas the promoter activity was inhibited 48 ± 5% by 100 nM 1α,25(OH)2D3. Our findings suggest that, unlike the renal enzyme, the prostate 1α-OHase appears to be largely unregulated by serum levels of PTH and calcium. These findings support the hypothesis that vitamin D or 25(OH)D may be useful as chemopreventive agents for prostate cancer because their administration should cause an increased synthesis of 1α,25(OH)2D within prostate cells.

carcinogenesis

The prostate 25-hydroxyvitamin D-1α-hydroxylase is not influenced by parathyroid hormone and calcium: implications for prostate cancer chemoprevention by vitamin D