This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kaeding, J. Articles by Barbier, O. Search for Related Content PubMed PubMed Citation Articles by Kaeding, J. Articles by Barbier, O.

Research Articles: Therapeutics, Targets, and Development

Calcitrol (1,25-dihydroxyvitamin D₃) inhibits androgen glucuronidation in prostate cancer cells

¹ Molecular Endocrinology and Oncology Research Center, Laval University Hospital Centre Research Center, ² Faculty of Pharmacy, and ³ Faculty of Medicine, Laval University, Sainte-Foy, Quebec, Canada

Requests for reprints: Olivier Barbier, Centre Hospitalier Universitaire de Québec-Laval University Hospital Centre Research Center, 2705, Boulevard Laurier, Sainte-Foy, Quebec G1V 4G2, Canada. Phone: 418-654-2296; Fax: 418-654-2769. E-mail: olivier.barbier{at}pha.ulaval.ca

Abstract

Calcitriol (1,25-dihydroxyvitamin D₃), the active metabolite of vitamin D, has recently emerged as a promising therapeutic agent in the treatment of prostate cancer, the second most common cause of cancer death in American males. In the present study, we have analyzed the effects of calcitriol treatment on the expression and activity of the UDP-glucuronosyltransferase (UGT) 2B15 and 2B17 in prostate cancer LNCaP and 22Rv1 cells. These two enzymes share a crucial role in the inactivation of androgens in the human prostate. We report that calcitriol treatment results in lower glucuronide conjugation of the active androgen dihydrotestosterone and its reduced metabolites androstane-3-diol and androsterone in LNCaP cells. The same treatment also drastically decreased the mRNA and protein levels of UGT2B15 and UGT2B17 in LNCaP and 22Rv1 cells. Using casodex, an androgen receptor (AR) antagonist, and AR-specific small interfering RNA probes, we show that calcitriol requires a functional AR to inhibit the expression of the UGT2B17 gene in LNCaP cells. By contrast, transient transfection and site-directed mutagenesis experiments revealed that calcitriol down-regulates UGT2B15 promoter activity through a responsive region between positions -171 and -113 bp. In conclusion, the present study identifies the vitamin D receptor activator calcitriol as a negative regulator of the UGT2B15- and UGT2B17-dependent inactivation of androgens in prostate cancer LNCaP cells. Androgens promote prostate cancer cell proliferation; thus, the reduction of their inactivation could have a limiting effect of the calcitriol antiproliferative properties in prostate cancer cells. [Mol Cancer Ther 2008;7(2):380–90]

Grant support: Canadian Institutes for Health Research MOP 118446 (O. Barbier), Fonds pour la Recherche en Santé du Québec (O. Barbier), Faculty of Pharmacy of Laval University (M. Verreault and J. Kaeding), and Health Research Foundation of R&D-Canadian Institutes for Health Research (O. Barbier and J. Kaeding).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Supplementary material for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 7/ 7/07; revised 12/ 4/07; accepted 12/31/07.