DELTA(5)-ANDROSTENEDIOL IS A NATURAL HORMONE WITH ANDROGENIC ACTIVITYIN HUMAN PROSTATE-CANCER CELLS

It is known that androst-5-ene-3 beta,17 beta-diol (Adiol), a precurso r of testosterone (T), can activate estrogen target genes. The androge nic activity of Adiol itself, however, is poorly understood. Using a t ransient transfection assay, we here demonstrate in human prostate can cer cells that Adiol can activate androgen receptor (AR) target genes in the presence of AR, and that AR coactivator ARA70 can further enhan ce this Adiol-induced AR transcriptional activity. In contrast to this finding, an active metabolite of dehydroepiandrosterone, 7-oxo-dehydr oepiandrosterone, does riot activate AR target gene in the absence or presence of ARA 70. Thin layer chromatography analysis reveals that T, dihydrotestosterone, and 17 beta-estradiol are undetectable in human prostate cancer DU145 cells after treatment with Adiol. Additionally, a proteolysis assay shows that a distinct ligand-receptor conformation al difference exists between T AR and Adiol-AR. Together, the above fi ndings and the fact that T, but not Adiol, can induce transcriptional activity in a mutant AR (mtAR708), suggest that, without being metabol ized into T, Adiol itself may represent a natural hormone with androge nic activity in human prostate cancer cells. Because two potent antian drogens, hydroxyflutamide (Eulexin), and bicalutamide (casodex), that are widely used for the treatment of prostate cancer, fail to block Ad iol-mediated induction of AR transcriptional activity in prostate canc er cells, the effectiveness of so-called ''total androgen blockage,'' a standard treatment for prostate cancer, may need to be reevaluated.