25-Hydroxyvitamin D3 is an agonistic vitamin D receptor ligand |
| |
| Authors: | Yan-Ru Lou Ferdinand Molnár Mikael Peräkylä Shengjun Qiao Allan V Kalueff René St-Arnaud Carsten Carlberg Pentti Tuohimaa |
| |
| Institution: | 1. Department of Anatomy, Medical School, University of Tampere, Tampere, FIN-33014, Finland;2. Division of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Helsinki, FIN-00014, Finland;3. Department of Biosciences, University of Kuopio, Kuopio, FIN-70211, Finland;4. Genetics Unit, Shriners Hospital for Children, Montréal, H3G 1A6, Canada;5. Life Science Research Unit, University of Luxembourg, L-1511, Luxembourg;6. Department of Clinical Chemistry, Tampere University Hospital, Tampere, FIN-33520, Finland;1. School of Pharmacy, University of Eastern Finland, Kuopio, Finland;2. Department of Neurology, University of Eastern Finland, Kuopio, Finland;3. Institute of Biomedical Technology, University of Tampere, Tampere, Finland;3. Departments of Pediatrics, Steele Children''s Research Center, University of Arizona Health Sciences Center, Tucson, Arizona 85724;5. Departments of Immunobiology, University of Arizona Health Sciences Center, Tucson, Arizona 85724;4. Zanvyl Krieger School of Arts and Sciences Johns Hopkins University, Baltimore, Maryland 21218;1. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China;2. Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, 402460, China;3. Chongqing Key Laboratory of Neurobiology, Chongqing, 400016, China;4. Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, 400016, China;5. College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China;6. Institute of Neuroscience, Basic Medical College, Chongqing Medical University, Chongqing, 400016, China;7. Key Laboratory of Laboratory Medical Diagnostics of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China;1. Department of Environmental Chemistry and Bioanalytics Faculty of Chemistry, Nicolaus Copernicus University, Gagarin 7, 87-100 Torun, Poland;2. Interdisciplinary Centre of Modern Technology, Nicolaus Copernicus University, Wileńska 4, 87-100 Toruń, Poland;3. Department of Chemical Engineering, Pukyong National University, 365 Sinseon-ro, 48-547, Busan, South Korea;1. UGC Cardiología, HUV Valme, Sevilla, Spain;2. Grupo de investigación en Osteoporosis y Metabolismo Mineral, Unidad Metabólica Ósea, Servicio de Medicina Interna, Hospital Universitario Insular de Las Palmas de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Spain;3. UGC Endocrinología y Nutrición HU Reina Sofía, Instituto Maimónides de Investigación Biomédica, Universidad de Córdoba, RETICEF, Spain |
| |
| Abstract: | 25-Hydroxyvitamin D3 1α-hydroxylase encoded by CYP27B1 converts 25-hydroxyvitamin D3 into 1α,25-dihydroxyvitamin D3, a vitamin D receptor ligand. 25-Hydroxyvitamin D3 has been regarded as a prohormone. Using Cyp27b1 knockout cells and a 1α-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 D3 has direct gene regulatory properties. The high expression of megalin, involved in 25-hydroxyvitamin D3 internalisation, in Cyp27b1?/? cells explains their higher sensitivity to 25-hydroxyvitamin D3. 25-Hydroxyvitamin D3 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 D3 and 1α,25-dihydroxyvitamin D3 with the larger volume of the ligand-binding pocket for 25-hydroxyvitamin D3. Furthermore, we demonstrate direct anti-proliferative effects of 25-hydroxyvitamin D3 in human LNCaP prostate cancer cells. The synergistic effect of 25-hydroxyvitamin D3 with 1α,25-dihydroxyvitamin D3 in Cyp27b1?/? cells further demonstrates the agonistic action of 25-hydroxyvitamin D3 and suggests that a synergism between 25-hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3 might be physiologically important. In conclusion, 25-hydroxyvitamin D3 is an agonistic vitamin D receptor ligand with gene regulatory and anti-proliferative properties. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
