Characterization of androgen-regulated expression of CYP3A5 in human prostate.
Testosterone is needed for the growth and development of the prostate. Androgen deprivation therapy is used for the treatment of prostate cancer. CYP3A5 is a human drug-metabolizing cytochrome P450 enzyme that metabolizes testosterone to the inactive 6beta-hydroxylated metabolite. We identified CYP3A5 as a novel androgen-regulated gene in human prostate by GeneChip analysis of human prostate tissues obtained from patients 3 days after therapeutic castration and from control patients. We further showed androgen induction of CYP3A5 messenger RNA (mRNA) in LNCaP prostate cancer cell line. Immunoblotting studies revealed CYP3A5 protein expression in all prostate samples studied. Immunohistochemistry and in situ hybridization was used for localization of CYP3A5 expression in prostate tissue. CYP3A5 was detected both in luminal and in basal epithelial cells of human prostate. Androgen response element was identified in the CYP3A5 proximal promoter and in electrophoretic mobility shift assay androgen receptor was found to bind this element. Androgen induction was abolished by mutation of the response element. We suggest that CYP3A5 is a part of an autoregulatory feedback loop controlling prostate cell exposure to androgens.
Moilanen
Anne-Mari
AM
Department of Pathology, University of Oulu and University Hospital of Oulu, FIN-90014 Oulu, Finland.
Hakkola
Jukka
J
Vaarala
Markku H
MH
Kauppila
Saila
S
Hirvikoski
Pasi
P
Vuoristo
Jussi T
JT
Edwards
Robert J
RJ
Paavonen
Timo K
TK
D000728:Androgens / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D040081:Protein Array Analysis; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D020218:Response Elements / Q000235:genetics
D000728:Androgens; D012333:RNA, Messenger; D011944:Receptors, Androgen; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A