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Glycogen Synthase Kinase-3ß Activity Is Required for Androgen-Stimulated Gene Expression in Prostate Cancer

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

Address all correspondence and requests for reprints to: Benyi Li, M.D., Ph.D., Department of Urology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160. E-mail: bli{at}kumc.edu.

Despite the specificity inferred by its name, glycogen synthase kinase (GSK)-3ß 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-3ß 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-3ß inhibitors, lithium chloride (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-3ß inhibitors in those cells. Most importantly, knocking down GSK-3ß expression via a small interference RNA-mediated gene silencing approach also reduced R1881-stimulated gene expression, demonstrating the specificity of GSK-3ß involvement. Moreover, R1881 treatment of the cells increased phosphorylation status of GSK-3ß on tyrosine residue Y²¹⁶ but not on serine residue S⁹. Pretreatment of the cells with phosphatidylinositol 3-kinase inhibitor LY294002 or wortmannin, which blocks androgen action in cells, abolished R1881-induced GSK-3ß Y²¹⁶ phosphorylation. However, the phosphatidylinositol 3kinase or GSK-3ß inhibitors did not block R1881-induced nuclear translocation of androgen receptor. Finally, knocking down the expression of Akt or ß-catenin, the two GSK-3ß-related signaling molecules, via siRNA-mediated gene silencing did not significant affect R1881-stimulated gene expression. These findings suggest that GSK-3ß activity is required for androgen-stimulated gene expression in prostate cancer cells.

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