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Submitted on February 23, 2006
Accepted on July 17, 2006
Oncology and Molecular Endocrinology Research Center, CHUL Research Center, 2705 Laurier Boul. Bloc T-3, Québec, Canada, G1V 4G2, Tel:418-654-2296, Fax:418-654-2761, Faculty of Medicine, Laval University, Faculty of Pharmacy, Laval University
* To whom correspondence should be addressed. E-mail: alain.belanger{at}ap.ulaval.ca or olivier.barbier{at}pha.ulaval.ca.
Androgens as well as monohydroxy-fatty acids are implicated in the pathogenesis of prostate cancer. As a huge variety of endo- and xenobiotics, they are eliminated as glucuronide conjugates formed by UDP-glucuronosyltransferase (UGT) enzymes. In the present study, we observe that treatment of the prostate cancer cells LNCaP with natural and synthetic androgens, interleukin-1
(IL-1) or epidermal growth factor (EGF) differently modulates the glucuronidation of androgen and bioactive lipid metabolites. Indeed, glucuronidation of 5-androstane-3, 17
-diol and 13-hydroxyoctadecadienoic acid was drastically reduced, whereas 12-hydroxyeicosatetraenoic acid conjugation by UGT was increased after androgen treatment. These effects reflected the reduction of UGT2B10, B15 and B17 enzyme expression, and the activation of the UGT2B11 gene. In human prostate epithelial cells (PrEC), only UGT2B11 and B15 mRNAs are detected, and are regulated by androgens in a similar manner as in LNCaP cells. In LNCaP cells, IL-1 and EGF also regulate UGT2B expression in an isoform specific manner: IL-1 induced UGT2B10 and reduces UGT2B17, while having no effects on UGT2B11 mRNA levels. EGF treatment resulted in a decreased UGT2B17 expression, whereas UGT2B10 and B11 mRNA remained at their basal levels. Overall, these results demonstrate that in the human prostate, androgens do not only affect their own inactivation, but also influence the levels of monohydroxy-fatty acids by regulating the expression of UGT2B enzymes in an isoform-specific manner. These differential effects of androgens, IL-1 and EGF on lipid metabolism likely constitute an additional mechanism by which these endogenous factors promote prostate cancer development.
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