TY - JOUR
T1 - 25-Hydroxyvitamin D3 is an agonistic vitamin D receptor ligand
AU - Lou, Yan Ru
AU - Molnár, Ferdinand
AU - Peräkylä, Mikael
AU - Qiao, Shengjun
AU - Kalueff, Allan V.
AU - St-Arnaud, René
AU - Carlberg, Carsten
AU - Tuohimaa, Pentti
PY - 2010/2/15
Y1 - 2010/2/15
N2 - 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.
AB - 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.
KW - Calcidiol
KW - Cellular growth
KW - CYP27B1
KW - Gene regulation
KW - Molecular dynamics simulation
UR - http://www.scopus.com/inward/record.url?scp=74449090261&partnerID=8YFLogxK
U2 - 10.1016/j.jsbmb.2009.11.011
DO - 10.1016/j.jsbmb.2009.11.011
M3 - Article
C2 - 19944755
AN - SCOPUS:74449090261
SN - 0960-0760
VL - 118
SP - 162
EP - 170
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
IS - 3
ER -