From transforming growth factor-beta signaling to androgen action: identification of Smad3 as an androgen receptor coregulator in prostate cancer cells

Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3018-23. doi: 10.1073/pnas.061305498. Epub 2001 Mar 6.


Although transforming growth factor-beta (TGF-beta) has been identified to mainly inhibit cell growth, the correlation of elevated TGF-beta with increasing serum prostate-specific antigen (PSA) levels in metastatic stages of prostate cancer has also been well documented. The molecular mechanism for these two contrasting effects of TGF-beta, however, remains unclear. Here we report that Smad3, a downstream mediator of the TGF-beta signaling pathway, functions as a coregulator to enhance androgen receptor (AR)-mediated transactivation. Compared with the wild-type AR, Smad3 acts as a strong coregulator in the presence of 1 nM 5alpha-dihydrotestosterone, 10 nM 17beta-estradiol, or 1 microM hydroxyflutamide for the LNCaP mutant AR (mtAR T877A), found in many prostate tumor patients. We further showed that endogenous PSA expression in LNCaP cells can be induced by 5alpha-dihydrotestosterone, and the addition of the Smad3 further induces PSA expression. Together, our findings establish Smad3 as an important coregulator for the androgen-signaling pathway and provide a possible explanation for the positive role of TGF-beta in androgen-promoted prostate cancer growth.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androgens / metabolism
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / physiology
  • Gene Expression
  • Humans
  • Male
  • Prostate-Specific Antigen / genetics
  • Prostatic Neoplasms
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Receptors, Calcitriol / metabolism
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Response Elements
  • Signal Transduction / physiology*
  • Smad3 Protein
  • Trans-Activators / metabolism*
  • Trans-Activators / physiology
  • Transcriptional Activation*
  • Transforming Growth Factor beta / metabolism*


  • Androgens
  • DNA-Binding Proteins
  • Receptors, Androgen
  • Receptors, Calcitriol
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Recombinant Fusion Proteins
  • SMAD3 protein, human
  • Smad3 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • Prostate-Specific Antigen