δ5-Androstenediol is a natural hormone with androgenic activity in human prostate cancer cells

H. Miyamoto, S. Yeh, H. Lardy, E. Messing, C. Chang

Research output: Contribution to journalArticle

Abstract

It is known that androst-5-ene-3β,17β-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 17β-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.

Original languageEnglish (US)
Pages (from-to)11083-11088
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number19
DOIs
StatePublished - Sep 15 1998

    Fingerprint

Keywords

  • 7-oxo-DHEA
  • ARA 70
  • Casodex
  • Hydroxyflutamide
  • Testosterone

ASJC Scopus subject areas

  • General

Cite this