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Reduced 1-hydroxylase Activity in Human Prostate Cancer Cells Correlates with Decreased Susceptibility to 25-Hydroxyvitamin D₃-induced Growth Inhibition¹

Departments of Medicine [J-Y. H., D. F.] and Urology [J. E. M., D. M. P.], Stanford University School of Medicine, Stanford, California 94305

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 D₃ [1,25(OH)₂D₃] was shown to exert antiproliferative, prodifferentiating, and antimetastatic/invasive effects on prostatic epithelial cells. Because the direct clinical application of 1,25(OH)₂D₃ is limited by the major side effect of hypercalcemia, we investigated the potential therapeutic utility of its less calcemic precursor, 25-hydroxyvitamin D₃ [25(OH)D₃], which is converted locally within the prostate to 1,25(OH)₂D₃ by 1-hydroxylase. Quantification of 1-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)D₃ inhibited growth of normal or BPH cells similarly to 1,25(OH)₂D₃. In contrast, in primary cultures of cancer cells and established cell lines, the antiproliferative action of 25(OH)D₃ was significantly less pronounced than that of 1,25(OH)₂D₃. Our results indicate that growth inhibition by 25(OH)D₃ depends on endogenous 1-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.

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