Retinoic acid via RARalpha 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 D3 (25OHD3) and 1alpha,25-dihydroxyvitamin D3 (1alpha,25-(OH)2D3) 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 1alpha,25-(OH)2D3 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 RARalpha but not by RARbeta. Moreover, the ATRA-induced expression of RARbeta was also mediated by RARalpha. The combined treatment of 1alpha,25-(OH)2D3 and RARalpha 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 RARalpha-dependent signaling pathway and can enhance vitamin D action in suppression of cell growth.
Lou
Yan-Ru
YR
Department of Anatomy Medical School, FIN-33014 University of Tampere, Finland. loyalo@uta.fi
Miettinen
Susanna
S
Kagechika
Hiroyuki
H
Gronemeyer
Hinrich
H
Tuohimaa
Pentti
P
D001565:Benzoates / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003984:Dibenzazepines; D004847:Epithelial Cells / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D011467:Prostate / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D011471:Prostatic Neoplasms; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors / Q000096:biosynthesis; D012176:Retinoids / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D065668:Vitamin D3 24-Hydroxylase
D001565:Benzoates; D003984:Dibenzazepines; C104182:LE 135; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C061133:tamibarotene; D014212:Tretinoin; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; C402892:BMS453