Partitioning of 5α-dihydrotestosterone and 5α-androstane- 3α, 17β-diol activated pathways for stimulating human prostate cancer LNCaP cell proliferation

Eva H. Nunlist, Igor Dozmorov, Yuhong Tang, Rick Cowan, Michael Centola, Hsueh Kung Lin

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

The growth and development of the prostate gland are regulated by androgens. Despite our understanding of molecular actions of 5α-dihydrotestosterone (5α-DHT) in the prostate through the trans-activation of the androgen receptor (AR), comprehensive analysis of androgen responsive genes (ARGs) has just been started. Moreover, expression changes induced by the androgen effects of 5α-androstane-3α, 17β-diol (3α-diol), a metabolite of 5α-DHT through the action of 3α-hydroxysteroid dehydrogenases (3α-HSDs), remain undefined. We demonstrated that both 5α-DHT and 3α-diol stimulated similar levels of androgen sensitive human prostate cancer LNCaP cell proliferation. However, consistent with the fact that 3α-diol has low affinity toward the AR, 3α-diol did not elicit the same levels of AR trans-activation activity as that of 5α-DHT. Since LNCaP cells respond to androgen stimulation by transcriptionally activating the AR downstream genes, gene expression patterns between 0 and 48 h following 3α-diol and 5α-DHT stimulation were analyzed using cDNA-based membrane arrays to define the temporal regulation of ARGs. Array analysis identified 217 and 219 androgen-modulated genes in at least one time point following 3α-diol and 5α-DHTstimulation, respectively, including key regulators of cell proliferation. Only a subset of these genes (143) was regulated by both androgens. These data suggest that 3α-diol exerts androgenic effects independent of the action of 5α-DHT in steroid target tissues. Accordingly, 3α-diol might activate cell proliferation cascades independent of AR pathway in the prostate.

Original languageEnglish (US)
Pages (from-to)157-170
Number of pages14
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume91
Issue number3
DOIs
StatePublished - Jul 2004

Keywords

  • 3α-Diol
  • 3α-HSD
  • 3α-hydroxysteroid dehydrogenase
  • 5α-androstane-3α,17β-diol
  • AR
  • ARE
  • ARG
  • DHT
  • androgen receptor
  • androgen response elements
  • androgen responsive gene

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

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