Search

The hormonal form of vitamin D, 1 alpha,25-dihydroxyvitamin D [1 alpha,25(OH)(2)D] promotes the differentiation and inhibits the proliferation, invasiveness and metastasis of prostate cells. However, 1 alpha,25(OH)(2)D is not suitable as a chemopreventive agent because its administration can cause hypercalcemia. Serum levels of 1 alpha,25(OH)(2)D are tightly regulated by the renal enzyme, 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-OHase), which synthesizes 1 alpha,25(OH)(2)D 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 1 alpha-OHase and synthesize the hormone intracellularly. We now investigated the regulation of the prostate 1 alpha-OHase by the three most important regulators of the renal 1 alpha-OHase: calcium, 1 alpha,25(OH)(2)D and parathyroid hormone (PTH). The 1 alpha-OHase activity in the primary cultures of prostate epithelial cells was inhibited by 1 alpha,25(OH)(2)D(3) at 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 1 alpha-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 1 alpha-OHase gene promoter activity in prostate cells, whereas the promoter activity was inhibited 48 +/- 5% by 100 nM 1 alpha,25(OH)(2)D(3). Our findings suggest that, unlike the renal enzyme, the prostate 1 alpha-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 1 alpha,25(OH)(2)D within prostate cells.

The steroid hormone 1,25-dihydroxyvitamin D(3), [1,25(OH)(2)D(3), calcitriol], the active metabolite of vitamin D, exerts pleiotropic antitumor effects against several malignancies. However, the clinical use of this hormone is limited by hypercalcemia. 25-Hydroxyvitamin D(3), the prohormone of 1,25(OH)(2)D(3), is hydroxylated to the active hormone by the enzyme 25-hydroxyvitamin-1-alpha-hydroxylase [1 alpha(OH)ase]. 1 alpha(OH)ase is found primarily in the kidney, but also is expressed in the prostate, colon and other tissues. Using immunohistochemistry, we report that 1 alpha(OH)ase is highly expressed in both normal and malignant pancreatic tissue. Expression of this enzyme and enzymatic activity was also detected in four pancreatic tumor cell lines. 25(OH)D(3) inhibited the growth of three of four pancreatic cell lines in a manner that correlated with the level of induction of the cyclin-dependent kinase inhibitors p21 and p27 and with the induction of cell cycle arrest at the G(1)/S checkpoint. The growth of a cell line stably transfected with a mutant Ki-ras allele and of a second cell line with an endogenous Ki-ras activating mutation was also inhibited by 25(OH)D(3), indicating that activating Ki-Ras mutations, which occur in almost 90% of pancreatic adenocarcinomas, do not interfere with the growth-inhibitory effects of 25(OH)D(3). The expression of 1 alpha(OH)ase in normal and malignant pancreatic tissue and the antiproliferative effects of the prohormone in these cells, suggest that 25(OH)D(3) may offer possible therapeutic and chemopreventive options for pancreatic cancer.