Abstract
Aberrant activation of the Wnt/β-catenin signaling pathway promotes osteosarcoma tumorigenesis and metastasis. In this study, we tested the hypothesis that osteosarcoma progression may be delayed by disrupting the Wnt/β-catenin pathway using small molecule inhibitors such as curcumin and PKF118-310. Effective inhibitions of the Wnt/β-catenin pathway by curcumin and PKF118-310 in osteosarcoma cells were shown by the suppression of both intrinsic and activated β-catenin/Tcf transcriptional activities using luciferase reporter assays. Western blot analysis revealed that there was no change in the amount of cytosolic β-catenin, although nuclear β-catenin was markedly reduced by treatment with either compounds. We next performed wound healing and Matrigel invasion assays and observed a dose-dependent decrease in osteosarcoma cell migration and invasion with curcumin and PKF118-310 treatment. Overexpression of the wild-type β-catenin plasmid in osteosarcoma cells resulted in enhanced cell invasiveness but this effect was significantly overcome by curcumin. Gelatin zymography and Western blotting showed that reduced cell invasion with curcumin and PKF118-310 treatment correlated with the activity and protein level of matrix metalloproteinase-9 under conditions of intrinsic or extrinsic Wnt/β-catenin activation. Using cell apoptosis assay and cell cycle analysis, we further showed that the anti-proliferative effect of PKF118-310 is attributed to PKF118-310-induced apoptosis and G2/M phase arrest. Lastly, we observed that these anti-cancer effects correlated with the decreased expression of cyclin D1, c-Myc and survivin. Our findings strongly suggest that curcumin and PKF118-310 have great therapeutic potential for the treatment of osteosarcoma.
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