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

Abstract

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.