Androgens are major regulators of prostate cell growth and physiology. In the human prostate, androgens are inactivated in the form of hydrophilic glucuronide conjugates. These metabolites are formed by the two human UGT2B15 [UGT (UDP-glucuronosyltransferase) 2B15] and UGT2B17 enzymes. The FXR (farnesoid X receptor) is a bile acid sensor controlling hepatic and/or intestinal cholesterol, lipid and glucose metabolism. In the present study, we report the expression of FXR in normal and cancer prostate epithelial cells, and we demonstrate that its activation by chenodeoxycholic acid or GW4064 negatively interferes with the levels of UGT2B15 and UGT2B17 mRNA and protein in prostate cancer LNCaP cells. FXR activation also causes a drastic reduction of androgen glucuronidation in these cells. These results point out activators of FXR as negative regulators of androgen-conjugating UGT expression in the prostate. Finally, the androgen metabolite androsterone, which is also an activator of FXR, dose-dependently reduces the glucuronidation of androgens catalysed by UGT2B15 and UGT2B17 in an FXR-dependent manner in LNCaP cells. In conclusion, the present study identifies for the first time the activators of FXR as important regulators of androgen metabolism in human prostate cancer cells.
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March 2008
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Research Article|
February 12 2008
Activators of the farnesoid X receptor negatively regulate androgen glucuronidation in human prostate cancer LNCAP cells
Jenny Kaeding;
Jenny Kaeding
*Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec, QC, Canada G1V 4G2
†Faculty of Pharmacy, Laval University, QC, Canada G1K 7P4
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Emmanuel Bouchaert;
Emmanuel Bouchaert
‡Unité 545 INSERM, Lille, Département d'athérosclérose, Institut Pasteur de Lille and Faculté de Pharmacie, Université Lille II, Lille F-59019, France
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Julie Bélanger;
Julie Bélanger
*Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec, QC, Canada G1V 4G2
†Faculty of Pharmacy, Laval University, QC, Canada G1K 7P4
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Patrick Caron;
Patrick Caron
*Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec, QC, Canada G1V 4G2
†Faculty of Pharmacy, Laval University, QC, Canada G1K 7P4
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Sarah Chouinard;
Sarah Chouinard
*Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec, QC, Canada G1V 4G2
§Faculty of Medicine, Laval University, QC, Canada G1K 7P4
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Mélanie Verreault;
Mélanie Verreault
*Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec, QC, Canada G1V 4G2
†Faculty of Pharmacy, Laval University, QC, Canada G1K 7P4
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Olivier Larouche;
Olivier Larouche
*Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec, QC, Canada G1V 4G2
§Faculty of Medicine, Laval University, QC, Canada G1K 7P4
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Georges Pelletier;
Georges Pelletier
*Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec, QC, Canada G1V 4G2
§Faculty of Medicine, Laval University, QC, Canada G1K 7P4
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Bart Staels;
Bart Staels
‡Unité 545 INSERM, Lille, Département d'athérosclérose, Institut Pasteur de Lille and Faculté de Pharmacie, Université Lille II, Lille F-59019, France
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Alain Bélanger;
Alain Bélanger
*Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec, QC, Canada G1V 4G2
§Faculty of Medicine, Laval University, QC, Canada G1K 7P4
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Olivier Barbier
Olivier Barbier
1
*Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec, QC, Canada G1V 4G2
†Faculty of Pharmacy, Laval University, QC, Canada G1K 7P4
1To whom correspondence should be addressed, at Laboratory of Transcriptomics and Molecular Pharmacology, CHUL Research Center (CHUQ), 2705, Blvd Laurier, Quebec, QC, Canada G1V 4G2 (email olivier.barbier@pha.ulaval.ca).
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Publisher: Portland Press Ltd
Received:
August 17 2007
Revision Received:
October 26 2007
Accepted:
November 07 2007
Accepted Manuscript online:
November 07 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 410 (2): 245–253.
Article history
Received:
August 17 2007
Revision Received:
October 26 2007
Accepted:
November 07 2007
Accepted Manuscript online:
November 07 2007
Citation
Jenny Kaeding, Emmanuel Bouchaert, Julie Bélanger, Patrick Caron, Sarah Chouinard, Mélanie Verreault, Olivier Larouche, Georges Pelletier, Bart Staels, Alain Bélanger, Olivier Barbier; Activators of the farnesoid X receptor negatively regulate androgen glucuronidation in human prostate cancer LNCAP cells. Biochem J 1 March 2008; 410 (2): 245–253. doi: https://doi.org/10.1042/BJ20071136
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