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 (GSK3β) inhibits Wnt signaling by inducing β-
catenin degradation, and a GSK3β 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, β-
catenin activation, proliferation, and apoptosis were assessed. Additionally,
prostate cancer and osteoblast cell lines were treated with AR79, and β-
catenin status, proliferation (with β-
catenin knockdown in some cases), and proportion of ALDH(+)CD133(+) stem-like cells were determined. AR79 promoted
prostate cancer tumor growth, decreased phospho-β-
catenin, increased total and nuclear β-
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 β-
catenin phosphorylation, increased nuclear β-
catenin accumulation in
prostate cancer and osteoblast cell lines, and increased proliferation of
prostate cancer cells in vitro through β-
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.
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