dihydrotestosterone-glucuronide and Prostatic-Neoplasms

It is now widely accepted that factors other than androgens are crucial in the normal and abnormal growth of the prostate. In addition to hormones, many polypeptide growth factors, including the fibroblast growth factor family (FGF), can act as potent mitogens on cell proliferation. The FGF family of growth factors are essential factors for both normal and abnormal proliferation of prostate cells. To study the effect of FGFs on steroid glucuronidation, we used the human prostate cancer LNCaP cell line which is known to be stimulated by FGF resulting in increased cell proliferation. LNCaP cells express steroid metabolizing enzymes including uridine diphosphoglucuronosyltransferases (UGTs). In addition, LNCaP cells treated with dihydrotestosterone (DHT) and epidermal growth factor (EGF) express differential levels of the human UGT2B15 and UGT2B17 transcripts. In the present study, we examined the possible interaction between FGF and steroid UGT enzymes. Results show a dose dependent inhibition of DHT glucuronide (DHT-G) formation following treatment (6 days) with acidic FGF (aFGF) and basic FGF (bFGF). When cells were treated with 10 ng/ ml of FGFs, we observed 33 and 51% inhibition of glucuronidation activity using aFGF and bFGF respectively. Ribonuclease protection analyses revealed a 2 and 3 fold increase of UGT2B15 mRNA expression following treatment with aFGF (50 ng/ml) and bFGF (10 ng/ml) respectively. However, a slight decrease in UGT2B17 transcripts was observed, demonstrating a differential regulation. Since a reduction in the glucuronidation of DHT or its 5alpha-reduced metabolites may contribute to an increase in intraprostatic androgen levels, down-regulation of UGTs by growth factors such as FGFs may increase the proliferation of androgen-dependent tumors.

Topics: Androgens; Cell Division; Dihydrotestosterone; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Gene Expression; Glucuronates; Glucuronosyltransferase; Humans; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; RNA, Messenger; RNA, Neoplasm; Steroids; Tumor Cells, Cultured

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.

Topics: Adenocarcinoma; Cell Division; Dihydrotestosterone; Glucuronosyltransferase; Humans; Hydroxysteroid Dehydrogenases; Male; Prostate-Specific Antigen; Prostatic Neoplasms; RNA, Messenger; Tumor Cells, Cultured