Effect of fibroblastic growth factors (FGF) on steroid UDP-glucuronosyltransferase expression and activity in the LNCaP cell line.
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.
Lévesque
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MRC Group in Molecular Endocrinology, CHUL Research Center and Laval University, Quebec, Canada.
Beaulieu
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Guillemette
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Hum
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Bélanger
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D000728:Androgens / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D013196:Dihydrotestosterone / Q000031:analogs & derivatives / Q000378:metabolism; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005965:Glucuronates / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D013256:Steroids / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000728:Androgens; D005965:Glucuronates; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013256:Steroids; D013196:Dihydrotestosterone; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; C037993:dihydrotestosterone glucuronide; D014453:Glucuronosyltransferase