Inhibition of prostate cancer growth by vitamin D: Regulation of target gene expression



Prostate cancer (PCa) cells express vitamin D receptors (VDR) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits the growth of epithelial cells derived from normal, benign prostate hyperplasia, and PCa as well as established PCa cell lines. The growth inhibitory effects of 1,25(OH)2D3 in cell cultures are modulated tissue by the presence and activities of the enzymes 25-hydroxyvitamin D3 24-hydroxylase which initiates the inactivation of 1,25(OH)2D3 and 25-hydroxyvitamin D3 1α-hydroxylase which catalyses its synthesis. In LNCaP human PCa cells 1,25(OH)2D3 exerts antiproliferative activity predominantly by cell cycle arrest through the induction of IGF binding protein-3 (IGFBP-3) expression which in turn increases the levels of the cell cycle inhibitor p21 leading to growth arrest. cDNA microarray analyses of primary prostatic epithelial and PCa cells reveal that 1,25(OH)2D3 regulates many target genes expanding the possible mechanisms of its anticancer activity and raising new potential therapeutic targets. Some of these target genes are involved in growth regulation, protection from oxidative stress, and cell–cell and cell–matrix interactions. A small clinical trial has shown that 1,25(OH)2D3 can slow the rate of prostate specific antigen (PSA) rise in PCa patients demonstrating proof of concept that 1,25(OH)2D3 exhibits therapeutic activity in men with PCa. Further investigation of the role of calcitriol and its analogs for the therapy or chemoprevention of PCa is currently being pursued. J. Cell. Biochem. 88: 363–371, 2003. © 2002 Wiley-Liss, Inc.