Document Detail

Mechanism of the anti-proliferative action of 25-hydroxy-19-nor-vitamin D(3) in human prostate cells.
MedLine Citation:
PMID:  21693624     Owner:  NLM     Status:  MEDLINE    
According to the prevailing paradigm, 1α-hydroxylation of 25-hydroxyvitamin D(3) (25(OH)D(3)) and its analogs is a pre-requisite step for their biological effects. We previously reported that 25-hydroxy-19-nor-vitamin D(3) (25(OH)-19-nor-D(3)) had anti-proliferative activity in a cell line, PZ-HPV-7, which was derived from human non-cancerous prostate tissue, and suggested that 25(OH)-19-nor-D(3) acted after 1α-hydroxylation by vitamin D 1α-hydroxylase (CYP27B1). However, metabolic studies of 25(OH)-19-nor-D(3) using recombinant CYP27B1 revealed that 25(OH)-19-nor-D(3) was rarely subjected to 1α-hydroxylation. Therefore, in this report, we attempted to clarify the mechanism of 25(OH)-19-nor-D(3) action in intact cells using PZ-HPV-7 prostate cells. After incubating the cells with 25(OH)-19-nor-D(3), eight metabolites of 24-hydroxylase (CYP24A1) were detected, whereas no products of CYP27B1 including 1α,25-dihydroxy-19-nor-vitamin D(3) (1α,25(OH)(2)-19-nor-D(3)) were found. Furthermore, the time-dependent nuclear translocation of vitamin D receptor (VDR) and the subsequent transactivation of cyp24A1 gene in the presence of 25(OH)-19-nor-D(3) were almost identical as those induced by 1α,25(OH)(2)-19-nor-D(3). These results strongly suggest that 25(OH)-19-nor-D(3) directly binds to VDR as a ligand and transports VDR into the nucleus to induce transcription of cyp24A1 gene. In addition, knock down of cyp27B1 gene did not affect the anti-proliferative activity of 25(OH)-19-nor-D(3), whereas knock down of VDR attenuated the inhibitory effect. Thus, our results clearly demonstrate that the anti-proliferative activity of 25(OH)-19-nor-D(3) is VDR dependent but 1α-hydroxylation independent, suggesting that 25(OH)D(3) analogs such as 25(OH)-19-nor-D(3) could be attractive candidates for anticancer therapy.
Eiji Munetsuna; Sachie Nakabayashi; Rie Kawanami; Kaori Yasuda; Miho Ohta; Midori A Arai; Atsushi Kittaka; Tai C Chen; Masaki Kamakura; Shinichi Ikushiro; Toshiyuki Sakaki
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-08-31
Journal Detail:
Title:  Journal of molecular endocrinology     Volume:  47     ISSN:  1479-6813     ISO Abbreviation:  J. Mol. Endocrinol.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-09-01     Completed Date:  2012-01-30     Revised Date:  2014-01-13    
Medline Journal Info:
Nlm Unique ID:  8902617     Medline TA:  J Mol Endocrinol     Country:  England    
Other Details:
Languages:  eng     Pagination:  209-18     Citation Subset:  IM    
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MeSH Terms
Blotting, Western
Calcitriol / pharmacology*
Cell Line
Cell Proliferation / drug effects
Protein Transport / drug effects,  genetics
RNA, Small Interfering
Receptors, Calcitriol / genetics,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
Steroid Hydroxylases / genetics,  metabolism
Reg. No./Substance:
0/RNA, Small Interfering; 0/Receptors, Calcitriol; 1C6V77QF41/Cholecalciferol; EC 1.14.-/Steroid Hydroxylases; EC D 24-hydroxylase; FXC9231JVH/Calcitriol

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