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Published on: September 18, 2013

Suppression of androgen receptor-mediated transactivation and cell growth by the glycogen synthase kinase 3 beta in

Liang Wang1, Hui-Kuan Lin, Yueh-Chiang Hu

  • 1George Whipple Laboratory for Cancer Research, Department of Pathology, University of Rochester Medical Center, New York 14642, USA.

The Journal of Biological Chemistry
|June 5, 2004
PubMed

Insights

Glycogen synthase kinase 3 beta (GSK3 beta) represses androgen receptor (AR) activity, inhibiting prostate cancer cell growth. This discovery offers a potential new therapeutic strategy for AR-mediated prostate cancer.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Signal Transduction

Background:

  • Androgen receptor (AR) signaling is crucial for normal prostate growth and prostate cancer development.
  • AR activity is modulated by androgens, growth factors, and kinases.

Purpose of the Study:

  • To investigate the role of glycogen synthase kinase 3 beta (GSK3 beta) in regulating androgen receptor (AR) transactivation and prostate cancer cell growth.

Main Methods:

  • Assessed AR transactivation in the presence of wild-type, constitutively active, and inactive GSK3 beta mutants.
  • Utilized GSK3 beta inhibitor (lithium chloride) to evaluate its effect on AR transactivation.
  • Performed in vitro kinase assays to determine GSK3 beta phosphorylation sites on AR.
  • Examined the effect of GSK3 beta on AR N- and C-terminal interactions and prostate cancer cell proliferation.

Main Results:

  • Wild-type and constitutively active GSK3 beta dose-dependently repressed AR transactivation, while inactive GSK3 beta had minimal effect.
  • GSK3 beta inhibition by lithium chloride abolished the suppression of AR transactivation.
  • GSK3 beta phosphorylates the N-terminus of AR, potentially inhibiting activation function 1 and disrupting AR N/C-terminal interaction.
  • Overexpression of active GSK3 beta reduced androgen-induced prostate cancer cell growth.

Conclusions:

  • GSK3 beta acts as a repressor of AR-mediated transactivation and prostate cancer cell growth.
  • Targeting GSK3 beta may offer a novel therapeutic strategy for managing AR-driven prostate cancer.

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