Inhibition of glycogen synthase kinase-3 represses androgen receptor activity and prostate cancer cell growth

Oncogene. 2004 Oct 14;23(47):7882-92. doi: 10.1038/sj.onc.1208068.


The transcriptional activity of the androgen receptor (AR) is regulated by interaction with various coregulators, one of which is beta-catenin. Interest in the role of beta-catenin in prostate cancer has been stimulated by reports showing that it is aberrantly expressed in the cytoplasm and/or nucleus in up to 38% of hormone-refractory tumours and that overexpression of beta-catenin results in activation of AR transcriptional activity. We have examined the effect of depleting endogenous beta-catenin on AR activity using Axin and RNA interference. Axin, which promotes beta-catenin degradation, inhibited AR transcriptional activity. However, this did not require the beta-catenin-binding domain of Axin. Depletion of beta-catenin using RNA interference increased, rather than decreased, AR activity, suggesting that endogenous beta-catenin is not a transcriptional coactivator for the AR. The glycogen synthase kinase-3 (GSK-3)-binding domain of Axin prevented formation of a GSK-3-AR complex and was both necessary and sufficient for inhibition of AR-dependent transcription. A second GSK-3-binding protein, FRAT, also inhibited AR transcriptional activity, as did the GSK-3 inhibitors SB216763 and SB415286. Finally, inhibition of GSK-3 reduced the growth of AR-expressing prostate cancer cell lines. Our observations suggest a potential new therapeutic application for GSK-3 inhibitors in prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminophenols / pharmacology
  • Base Sequence
  • Cell Division / drug effects
  • Cytoskeletal Proteins / physiology
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Neoplastic
  • Glycogen Synthase Kinase 3 / genetics*
  • Humans
  • Indoles / pharmacology
  • Male
  • Maleimides / pharmacology
  • Molecular Sequence Data
  • Polydeoxyribonucleotides
  • Prostatic Neoplasms / pathology*
  • RNA, Small Interfering / genetics
  • Receptors, Androgen / genetics*
  • Trans-Activators / physiology
  • beta Catenin


  • 3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
  • Aminophenols
  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • Enzyme Inhibitors
  • Indoles
  • Maleimides
  • Polydeoxyribonucleotides
  • RNA, Small Interfering
  • Receptors, Androgen
  • SB 216763
  • Trans-Activators
  • beta Catenin
  • Glycogen Synthase Kinase 3