The Role of Vitamin D in Prostate Cancer

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Abstract
Prostate cancer (PCa) cells harbor receptors for vitamin D (VDR) as well as androgens (AR). 1,25-dihydroxyvitamin D3[1,(OH)2D3] increases AR expression and enhances androgen actions linking the two receptor systems.1,(OH)2D3exhibits antiproliferative activity in both AR-positive and AR-negative PCa cells. Less calcemic analogs of 1,(OH)2D3, with more antiproliferative activity, are being developed and will be more useful clinically. The mechanisms underlying differential analog activity are being investigated. In target cells, 1,(OH)2D3induces 24-hydroxylase, the enzyme that catalyzes its selfinactivation.Co-treatment with 24-hydroxylase inhibitors enhances the antiproliferative activity of calcitriol. Primary cultures of normal or cancer-derived prostatic epithelial cells express 1a-hydroxylase, the enzyme that catalyzes the synthesis of 1,(OH)2D3, the levels being much lower in the cancerderived cells and in PCa cell lines. This finding raises the possibility of using 25-hydroxyvitamin D3[25(OH)D3] as a chemopreventive agent in PCa.In LNCaP human PCa cells, 1,(OH)2D3and its analogs exert antiproliferative activity predominantly by cell cycle arrest, but also induce apoptosis, although to a much lesser degree. Growth arrest is mediated by induction of IGF binding protein-3 (IGFBP-3), which in turn increases the expression of the cell cycle inhibitor p21, leading to growth arrest. Other actions of 1,(OH)2D3in PCa cells include promotion of pro-differentiation effects and inhibition of tumor cell invasion,metastasis and angiogenesis.