title: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand.
abstract: 25-Hydroxyvitamin D(3) 1alpha-hydroxylase encoded by CYP27B1 converts 25-hydroxyvitamin D(3) into 1alpha,25-dihydroxyvitamin D(3), a vitamin D receptor ligand. 25-Hydroxyvitamin D(3) has been regarded as a prohormone. Using Cyp27b1 knockout cells and a 1alpha-hydroxylase-specific inhibitor we provide in four cellular systems, primary mouse kidney, skin, prostate cells and human MCF-7 breast cancer cells, evidence that 25-hydroxyvitamin D(3) has direct gene regulatory properties. The high expression of megalin, involved in 25-hydroxyvitamin D(3) internalisation, in Cyp27b1(-/-) cells explains their higher sensitivity to 25-hydroxyvitamin D(3). 25-Hydroxyvitamin D(3) action depends on the vitamin D receptor signalling supported by the unresponsiveness of the vitamin D receptor knockout cells. Molecular dynamics simulations show the identical binding mode for both 25-hydroxyvitamin D(3) and 1alpha,25-dihydroxyvitamin D(3) with the larger volume of the ligand-binding pocket for 25-hydroxyvitamin D(3). Furthermore, we demonstrate direct anti-proliferative effects of 25-hydroxyvitamin D(3) in human LNCaP prostate cancer cells. The synergistic effect of 25-hydroxyvitamin D(3) with 1alpha,25-dihydroxyvitamin D(3) in Cyp27b1(-/-) cells further demonstrates the agonistic action of 25-hydroxyvitamin D(3) and suggests that a synergism between 25-hydroxyvitamin D(3) and 1alpha,25-dihydroxyvitamin D(3) might be physiologically important. In conclusion, 25-hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand with gene regulatory and anti-proliferative properties.
authors: Department of Anatomy, Medical School, University of Tampere, Tampere, FIN-33014, Finland. yan-ru.lou@helsinki.fi <yan-ru.lou@helsinki.fi>
authors: Yan-Ru
authors: YR
authors: Lou
authors: Ferdinand
authors: F
authors: Molnár
authors: Mikael
authors: M
authors: Peräkylä
authors: Shengjun
authors: S
authors: Qiao
authors: Allan V
authors: AV
authors: Kalueff
authors: René
authors: R
authors: St-Arnaud
authors: Carsten
authors: C
authors: Carlberg
authors: Pentti
authors: P
authors: Tuohimaa
mesh_terms: D015650:24,25-Dihydroxyvitamin D 3 / Q000494:pharmacology; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D002112:Calcifediol / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002117:Calcitriol / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000166:cytology; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D056004:Molecular Dynamics Simulation; D011467:Prostate / Q000166:cytology; D017434:Protein Structure, Tertiary; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D012867:Skin / Q000166:cytology; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D004791:Enzyme Inhibitors; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D018167:Receptors, Calcitriol; D015650:24,25-Dihydroxyvitamin D 3; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002112:Calcifediol