Reduced 1 alpha-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D-3-induced growth inhibition

Evidence from epidemiological, molecular, and genetic studies suggests a ro le 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 a ntimetastatic/invasive effects on prostatic epithelial cells, Because the d irect clinical application of 1,25(OH)(2)D-3 is limited by the major side e ffect of hypercalcemia, we investigated the potential therapeutic utility o f its less calcemic precursor, 25-hydroxyvitamin D, [25(OH)D-3], which is c onverted locally within the prostate to 1,25(OH)(2)D-3 by 1 alpha -hydroxyl ase. Quantification of 1 alpha -hydroxylase activity; in human prostatic ep ithelial cells by enzyme-substrate reaction analyses revealed a significant ly decreased activity in cells derived from adenocarcinomas compared with c ells 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 ce lls 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 result s indicate that growth inhibition by 25(OH)D-3 depends on endogenous 1 alph a -hydroxylase activity, and that this activity is deficient in prostate ca ncer cells. This finding has ramifications for both the prevention and ther apy of prostate cancer with vitamin D compounds.