Reduced 1α-hydroxylase Activity in Human Prostate Cancer Cells Correlates with Decreased Susceptibility to 25-Hydroxyvitamin D3-induced Growth Inhibition

Evidence from epidemiological, molecular, and genetic studies suggests a role for vitamin D in the development and/or progression of prostate cancer. In experimental models and clinical trials, 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] was shown to exert antiproliferative, prodifferentiating, and antimetastatic/invasive effects on prostatic epithelial cells. Because the direct clinical application of 1,25(OH) 2 D 3 is limited by the major side effect of hypercalcemia, we investigated the potential therapeutic utility of its less calcemic precursor, 25-hydroxyvitamin D 3 [25(OH)D 3 ], which is converted locally within the prostate to 1,25(OH) 2 D 3 by 1α-hydroxylase. Quantification of 1α-hydroxylase activity in human prostatic epithelial cells by enzyme-substrate reaction analyses revealed a significantly decreased activity in cells derived from adenocarcinomas compared with cells derived from normal tissues or benign prostatic hyperplasia (BPH). In growth assays, we found that 25(OH)D 3 inhibited growth of normal or BPH cells similarly to 1,25(OH) 2 D 3 . In contrast, in primary cultures of cancer cells and established cell lines, the antiproliferative action of 25(OH)D 3 was significantly less pronounced than that of 1,25(OH) 2 D 3 . Our results indicate that growth inhibition by 25(OH)D 3 depends on endogenous 1α-hydroxylase activity, and that this activity is deficient in prostate cancer cells. This finding has ramifications for both the prevention and therapy of prostate cancer with vitamin D compounds.