Analysis of vitamin D-regulated gene expression in LNCaP human prostate cancer cells using cDNA microarrays

BACKGROUND. 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] exerts growth inhibitory, pro-differentiating, and pro-apoptotic effects on prostate cells. To better understand the molecular mechanisms underlying these actions, we employed cDNA microarrays to study 1,25(OH)(2)D-3-regulated gene expression in the LNCaP human prostate cancer cells. METHODS. mRNA isolated from LNCaP cells treated with vehicle or 50 nM 1,25(OH)(2)D-3 for various lengths of time were hybridized to microarrays carrying approximately 23,000 genes. Some of the putative target genes revealed by the microarray analysis were verified by real-time PCR assays. RESULTS. 1,25(OH)(2)D-3 most substantially increased the expression of the insulin-like growth factor binding protein-3 (IGFBP-3) gene. Our analysis also revealed several novel 1,25(OH)(2)D-3-responsive genes. Interestingly, some of the key genes regulated by 1,25(OH)(2)D-3 are also androgen-responsive genes. 1,25(OH)(2)D-3 also down-regulated genes that mediate androgen catabolism. CONCLUSIONS. The putative 1,25(OH)(2)D-3 target genes appear to be involved in a variety of cellular functions including growth regulation, differentiation, membrane transport, cell-cell and cell-matrix interactions, DNA repair, and inhibition of metastasis. The up-regulation of IGFBP-3 gene has been shown to be crucial in 1,25(OH)(2)D-3-mediated inhibition of LNCaP cell growth. 1,25(OH)(2)D-3 regulation of androgen-responsive genes as well as genes involved in androgen catabolism suggests that there are interactions between 1,25(OH)(2)D-3 and androgen signaling pathways in LNCaP cells. Further studies on the role of these genes and others in mediating the anti-cancer effects of 1,25(OH)(2)D-3 may lead to better approaches to the prevention and treatment of prostate cancer. (C) 2003 Wiley-Liss. Inc.