Mechanism of the anti-proliferative action of 25-hydroxy-19-nor-vitamin D 3 in human prostate cells

Eiji Munetsuna, Sachie Nakabayashi, Rie Kawanami, Kaori Yasuda, Miho Ohta, Midori A. Arai, Atsushi Kittaka, Tai C. Chen, Masaki Kamakura, Shinichi Ikushiro, Toshiyuki Sakaki

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

According to the prevailing paradigm, 1α-hydroxylation of 25-hydroxyvitamin D 3 (25(OH)D 3) and its analogs is a prerequisite 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 1a-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 1a,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.

Original languageEnglish
Pages (from-to)209-218
Number of pages10
JournalJournal of Molecular Endocrinology
Volume47
Issue number2
DOIs
Publication statusPublished - 10-2011

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

Fingerprint Dive into the research topics of 'Mechanism of the anti-proliferative action of 25-hydroxy-19-nor-vitamin D <sub>3</sub> in human prostate cells'. Together they form a unique fingerprint.

Cite this