Evidence for a role of glucuronosyltransferase in the regulation of androgen action in the human prostatic cancer cell line LNCaP.
Androgens play an important role in the regulation of cell growth and specific protein synthesis in hormone-sensitive prostatic cancer. In this study, we have investigated the metabolism of androgens in LNCaP cells from low passage (LP) and high passage (HP) cultures which were previously shown to possess differential androgen responsiveness. When treated with dihydrotestosterone (DHT), cells showed the characteristic biphasic response of cell proliferation with an ED50 of 1 nM for both the LP and HP cells, but the maximal proliferative response was different with values of 2.65- and 4.29-fold over basal for LP and HP cells, respectively. Metabolism studies indicated no difference in 5alpha-reductase activity between LP and HP cells, while 3alpha-, 3beta- and 17beta-hydroxysteroid dehydrogenase activities were significantly higher in LP cultures. The formation of steroid glucuronides (-G), namely DHT-G, was higher in LP than in HP cells with values of 2.16 and 1.31 pmol of glucuronides formed/microgram DNA/3 h, respectively. Northern blot analysis with a UGT21B15 cDNA probe identified two bands corresponding to two or more UGT transcripts in both LNCaP cells and more transcript was observed in LP than in HP cells. Taken together these results indicate that DHT is deactivated more rapidly in the LP cells, which may explain in part the lower proliferative response to androgens of LP cells compared with HP cells.
Guillemette
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MRC Group in Molecular Endocrinology, CHUL Research Center and Laval University, Quebec, Canada.
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Bélanger
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D000230:Adenocarcinoma / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D008297:Male; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D013196:Dihydrotestosterone; C037993:dihydrotestosterone glucuronide; D006913:Hydroxysteroid Dehydrogenases; D014453:Glucuronosyltransferase; D017430:Prostate-Specific Antigen