title: Androgen receptor signals regulate UDP-glucuronosyltransferases in the urinary bladder: a potential mechanism of androgen-induced bladder carcinogenesis.
abstract: UDP-glucuronosyltransferases (UGTs), major phase II drug metabolism enzymes, play an important role in urinary bladder cancer initiation by detoxifying carcinogens. We aimed to determine if androgens regulate UGT expression via the androgen receptor (AR) pathway in the bladder. Real-time reverse transcription-polymerase chain reaction and Western blot analyses were used to assess UGT1A levels in the normal urothelium SVHUC cell line stably expressed with AR and in bladder tissues from AR knockout (ARKO) and castrated male mice. Immunohistochemistry was also performed in radical cystectomy specimens. Dihydrotestosterone (DHT) treatment in SVHUC-AR reduced mRNA expression of all the UGT1A subtypes (19-75% decrease), and hydroxyflutamide antagonized the DHT effects. In contrast, DHT showed only marginal effects on UGT1A expression in SVHUC-Vector. Of note were higher expression levels of UGT1As in SVHUC-Vector than in SVHUC-AR. In ARKO mice, all the Ugt1a subtypes were up-regulated, compared to wild-type littermates. In wild-type male mice, castration increased the expression of Ugt1a8, Ugt1a9, and Ugt1a10. Additionally, wild-type female mice had higher levels of Ugt1a than wild-type males. Immunohistochemical studies showed strong (3+) UGT1A staining in 11/24 (46%) cancer tissues, which was significantly lower than in corresponding benign tissues [17/18 (94%) cases (P = 0.0009)]. These results suggest that androgen-mediated AR signals promote bladder carcinogenesis by down-regulating the expression of UGTs in the bladder.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Izumi
authors.forename: Yichun
authors.initials: Y
authors.lastname: Zheng
authors.forename: Jong-Wei
authors.initials: JW
authors.lastname: Hsu
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyamoto
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D015653:Cystectomy; D013196:Dihydrotestosterone / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D005485:Flutamide / Q000031:analogs & derivatives / Q000494:pharmacology; D005500:Follow-Up Studies; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009919:Orchiectomy; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012016:Reference Values; D015398:Signal Transduction; D000090264:UDP-Glucuronosyltransferase 1A9; D001743:Urinary Bladder / Q000166:cytology / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D000099148:UGT1A1 Enzyme
chemical_list: D000726:Androgen Antagonists; D013196:Dihydrotestosterone; D005485:Flutamide; D014453:Glucuronosyltransferase; D011944:Receptors, Androgen; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C410798:AR protein, human; C000715591:UGT1A9 protein, human; C000715592:Ugt1a9 protein, mouse; C014290:hydroxyflutamide; C454320:UDP-glucuronosyltransferase, UGT1A8