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

Abstract

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 1α,25-dihydroxyvitamin D 3 (1α,25-(OH) 2D 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 25OHD 3 and 1α,25-(OH) 2D 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 RARα but not by RARβ. Moreover, the ATRA-induced expression of RARβ was also mediated by RARα. The combined treatment of 1α,25-(OH) 2D 3 and RARα 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 RARα-dependent signaling pathway and can enhance vitamin D action in suppression of cell growth.