Activators of the farnesoid X-receptor negatively regulate androgen glucuronidation in human prostate cancer LNCaP cells.

The Biochemical journal 2007 Nov 7; In press

Kaeding J J, Bouchaert E E, Bélanger J J, Caron P P, Chouinard S S, Verreault M M, Larouche O O, Pelletier G G, Staels B B, Bélanger A A, Barbier O O

Androgens are major regulators of prostate cell growth and physiology. In the human prostate, androgens are inactivated under the form of hydrophilic glucuronide conjugates. These metabolites are formed by the two human UDP-glucuronosyltransferase (UGT) 2B15 and UGT2B17 enzymes. The farnesoid X-receptor (FXR) 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 data 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 catalyzed 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.

Keywords: prostate cancer