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This version published online on February 26, 2004
Endocrinology, doi:10.1210/en.2003-1519
A more recent version of this article appeared on June 1, 2004
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Submitted on November 10, 2003
Accepted on February 18, 2004

GSK-3{beta} activity is required for androgen-stimulated gene expression in prostate cancer

Xinbo Liao, J. Brantley Thrasher, Jeffery Holzbeierlein, Scott Stanley, and Benyi Li*

Department of Urology and Kansas Cancer Institute, The University of Kansas Medical Center, Kansas City, Kansas 66160

* To whom correspondence should be addressed. E-mail: bli{at}kumc.edu.

Despite the specificity inferred by its name, GSK-3{beta} is an important kinase with a plethora of significant cellular targets, including cytoskeletal proteins and transcription factors, and its activity is regulated by phosphorylation on tyrosine/serine residues. As part of our efforts to dissect the molecular basis responsible for androgen-independent progression of prostate cancer, we investigated the role of GSK-3{beta} in androgen-stimulated gene expression in human prostate cancer cells. Pretreatment of prostate cancer cells harboring wild-type or mutant androgen receptor with the GSK-3{beta} inhibitors, LiCl, RO318220, or GF109203X inhibited R1881-stimulated androgen responsive reporter activity in a dose- and time-dependent manner. In addition, the expression of two endogenous androgen-stimulated gene products, prostate-specific antigen and matrix metalloproteinase-2, was suppressed by the GSK-3{beta} inhibitors in those cells. Most importantly, knocking down GSK-3{beta} expression via a small interference RNA-mediated gene silencing approach also reduced R1881-stimulated gene expression, demonstrating the specificity of GSK-3{beta} involvement. Moreover, R1881 treatment of the cells increased phosphorylation status of GSK-3{beta} on tyrosine residue Y216 but not on serine residue S9. Pretreatment of the cells with PI3K inhibitor LY294002 or wortmannin, which blocks androgen action in cells, abolished R1881-induced GSK-3{beta} Y216 phosphorylation. However, the PI3K or GSK-3{beta} inhibitors did not block R1881-induced nuclear translocation of androgen receptor. Finally, knocking down the expression of Akt or {beta}-catenin, the two GSK-3{beta}-related signaling molecules, via siRNA-mediated gene silencing did not significant affect R1881-stimulated gene expression. These findings suggest that GSK-3{beta} activity is required for androgen-stimulated gene expression in prostate cancer cells.
Key words: androgen • rogen receptor • GSK-3{beta} • PI3 kinase • prostate cancer




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