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

Despite the specificity inferred by its name, glycogen synthase kinase (GSK)-3β 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-3β 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-3β 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-3β inhibitors in those cells. Most importantly, knocking down GSK-3β ex...