Activation of the Wnt Pathway through AR79, a GSK3? Inhibitor, Promotes Prostate Cancer Growth in Soft Tissue and Bone.
Due to its bone anabolic activity, methods to increase Wnt activity, such as inhibitors of dickkopf-1 and sclerostin, are being clinically explored. Glycogen synthase kinase (GSK3?) inhibits Wnt signaling by inducing ?-catenin degradation, and a GSK3? inhibitor, AR79, is being evaluated as an osteoanabolic agent. However, Wnt activation has the potential to promote tumor growth; therefore, the goal of this study was to determine if AR79 has an impact on the progression of prostate cancer. Prostate cancer tumors were established in subcutaneous and bone sites of mice followed by AR79 administration, and tumor growth, ?-catenin activation, proliferation, and apoptosis were assessed. Additionally, prostate cancer and osteoblast cell lines were treated with AR79, and ?-catenin status, proliferation (with ?-catenin knockdown in some cases), and proportion of ALDH(+)CD133(+) stem-like cells were determined. AR79 promoted prostate cancer tumor growth, decreased phospho-?-catenin, increased total and nuclear ?-catenin, and increased tumor-induced bone remodeling. Additionally, AR79 treatment decreased caspase-3 and increased Ki67 expression in tumors and increased bone formation in normal mouse tibiae. Similarly, AR79 inhibited ?-catenin phosphorylation, increased nuclear ?-catenin accumulation in prostate cancer and osteoblast cell lines, and increased proliferation of prostate cancer cells in vitro through ?-catenin. Furthermore, AR79 increased the ALDH(+)CD133(+) cancer stem cell-like proportion of the prostate cancer cell lines. In conclusion, AR79, while being bone anabolic, promotes prostate cancer cell growth through Wnt pathway activation. Implications: These data suggest that clinical application of pharmaceuticals that promote Wnt pathway activation should be used with caution as they may enhance tumor growth. Mol Cancer Res; 11(12); 1597-610. ©2013 AACR.