Molecular activity of 1,25-dihydroxyvitamin D 3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis

Abstract

1,25-Dihydroxyvitamin D 3 [1,25(OH) 2D 3] exerts anti-proliferative, differentiating and apoptotic effects on prostatic cells. These activities, in addition to epidemiologic findings that link Vitamin D to prostate cancer risk, support the use of 1,25(OH) 2D 3 for prevention or therapy of prostate cancer. The molecular mechanisms by which 1,25(OH) 2D 3 exerts antitumor effects on prostatic cells are not well-defined. In addition, there is heterogeneity among the responses of various prostate cell lines and primary cultures to 1,25(OH) 2D 3 with regard to growth inhibition, differentiation and apoptosis. To understand the basis of these differential responses and to develop a better model of Vitamin D action in the prostate, we performed cDNA microarray analyses of primary cultures of normal and malignant human prostatic epithelial cells, treated with 50 nM of 1,25(OH) 2D 3 for 6 and 24 h. CYP24 (25-hydroxyvitamin D 3-24-hydroxylase) was the most highly upregulated gene. Significant and early upregulation of dual specificity phosphatase 10 (DUSP10), validated in five additional primary cultures, points to inhibition of members of the mitogen-activated protein kinase (MAPK) superfamily as a key event mediating activity of 1,25(OH) 2D 3 in prostatic epithelial cells. The functions of other regulated genes suggest protection by 1,25(OH) 2D 3 from oxidative stress. Overall, these results provide new insights into the molecular basis of antitumor activities of Vitamin D in prostate cells.