Suppression of androgen receptor-mediated transactivation and cell growth by the glycogen synthase kinase 3 beta in prostate cells.
Androgens play important roles in the growth of normal prostate and prostate cancer via binding to the androgen receptor (AR). In addition to androgens, AR activity can also be modulated by selective growth factors and/or kinases. Here we report a new kinase signaling pathway by showing that AR transactivation was repressed by wild type glycogen synthase kinase 3beta (GSK3 beta) or constitutively active S9A-GSK3 beta in a dose-dependent manner. In contrast, the catalytically inactive kinase mutant GSK3 beta showed little effect on the AR transactivation. The suppression of AR transactivation by GSK3 beta was abolished by the GSK3 beta inhibitor lithium chloride. The in vitro kinase assay showed that GSK3 beta prefers to phosphorylate the amino terminus of AR that may lead to the suppression of activation function 1 activity located in the NH(2)-terminal region of AR. GSK3 beta interrupted the interaction between the NH(2) and COOH termini of AR, and overexpression of the constitutively active form of GSK3 beta, S9A-GSK3 beta, reduced the androgen-induced prostate cancer cell growth in stably transfected CWR22R cells. Together, our data demonstrated that GSK3 beta may function as a repressor to suppress AR-mediated transactivation and cell growth, which may provide a new strategy to modulate the AR-mediated prostate cancer growth.
Wang
Liang
L
George Whipple Laboratory for Cancer Research, Department of Pathology, University of Rochester Medical Center, New York 14642, USA.
Lin
Hui-Kuan
HK
Hu
Yueh-Chiang
YC
Xie
Shaozhen
S
Yang
Lin
L
Chang
Chawnshang
C
D000818:Animals; D019556:COS Cells; D002384:Catalysis; D002455:Cell Division; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008024:Ligands; D008297:Male; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection
D008024:Ligands; D011944:Receptors, Androgen; D013778:Tetrazolium Salts; D013844:Thiazoles; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C022616:thiazolyl blue