Delta5-androstenediol is a natural hormone with androgenic activity in human prostate cancer cells.
It is known that androst-5-ene-3beta,17beta-diol (Adiol), a precursor of testosterone (T), can activate estrogen target genes. The androgenic activity of Adiol itself, however, is poorly understood. Using a transient transfection assay, we here demonstrate in human prostate cancer cells that Adiol can activate androgen receptor (AR) target genes in the presence of AR, and that AR coactivator ARA70 can further enhance this Adiol-induced AR transcriptional activity. In contrast to this finding, an active metabolite of dehydroepiandrosterone, 7-oxo-dehydroepiandrosterone, does not activate AR target gene in the absence or presence of ARA70. Thin layer chromatography analysis reveals that T, dihydrotestosterone, and 17beta-estradiol are undetectable in human prostate cancer DU145 cells after treatment with Adiol. Additionally, a proteolysis assay shows that a distinct ligand-receptor conformational difference exists between T-AR and Adiol-AR. Together, the above findings and the fact that T, but not Adiol, can induce transcriptional activity in a mutant AR (mtAR708), suggest that, without being metabolized into T, Adiol itself may represent a natural hormone with androgenic activity in human prostate cancer cells. Because two potent antiandrogens, hydroxyflutamide (Eulexin), and bicalutamide (casodex), that are widely used for the treatment of prostate cancer, fail to block Adiol-mediated induction of AR transcriptional activity in prostate cancer cells, the effectiveness of so-called "total androgen blockage," a standard treatment for prostate cancer, may need to be reevaluated.
Miyamoto
H
H
George Whipple Laboratory for Cancer Research, Department of Pathology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, NY 14642, USA.
Yeh
S
S
Lardy
H
H
Messing
E
E
Chang
C
C
D000728:Androgens / Q000502:physiology*; D015113:Androstane-3,17-diol / Q000031:analogs & derivatives; D015114:Androstenediol / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D005485:Flutamide / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008297:Male; D009154:Mutation; D009570:Nitriles; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000628:therapy; D011487:Protein Conformation / Q000187:drug effects; D011944:Receptors, Androgen / Q000378:metabolism; D013256:Steroids / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D014105:Tosyl Compounds; D015534:Trans-Activators / Q000494:pharmacology; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection / Q000235:genetics; D014407:Tumor Cells, Cultured
D000728:Androgens; D000813:Anilides; C111382:NCOA4 protein, human; D009570:Nitriles; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D011944:Receptors, Androgen; D013256:Steroids; D014105:Tosyl Compounds; D015534:Trans-Activators; D014157:Transcription Factors; C038884:androstane-3,17-diol receptor; D015113:Androstane-3,17-diol; C014290:hydroxyflutamide; D013739:Testosterone; D005485:Flutamide; D015114:Androstenediol; C053541:bicalutamide