Retinoic acid via RARα inhibits the expression of 24-hydroxylase in human prostate stromal cells

25-Hydroxyvitamin D-3-24-hydroxylase (24-hydroxylase) is an important inactivating enzyme and its expression is induced by 25-hydroxyvitamin D-3 (25OHD(3)) and 1 alpha,25-dihydroxyvitamin D-3 (1 alpha,25-(OH)(2)D-3) through action of heterodimers of vitamin D receptor (VDR) and retinoid X receptor (RXR). RXRs also act as heterodimer partners for retinoic acid receptors (RARs), mediating the action of all-trans-retinoic acid (ATRA). Prostate stroma plays a crucial role in prostate cancer development and benign prostatic hyperplasia. We demonstrate here that ATRA markedly reduced the expression of 24-hydroxylase mRNA induced by 25OHD3 and 1 alpha,25-(OH)(2)D-3 in human prostatic stromal cells P29SN and P32S but not in epithelial cells PrEC or cancer cells LNCaP. By using transfection and RAR-selective ligands, we found that the inhibitory effect of ATRA on 24-hydroxylase expression in stromal cells was mediated by RAR alpha but not by RAR beta. Moreover, the ATRA-induced expression of RAR beta was also mediated by RAR-alpha. The combined treatment of 1 alpha,25(OH)(2)D-3 and RAR alpha agonist Am80 at 10 nM exhibited strong growth-inhibitory effect whereas either alone had no effect. Our data suggest that ATRA suppresses 24-hydroxylase expression through RAR alpha-dependent signaling pathway and can enhance vitamin D action in suppression of cell growth. (c) 2005 Elsevier Inc. All rights reserved.