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API-2-Induced Cell Migration Is Overcome by Small Molecular Approaches Inhibiting β-Catenin
Authors:Yonghyo Kim  Myoung-Hee Kang  Yong-Hee Cho
Affiliation:1.Data Convergence Drug Research Center, Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea;2.Department of Plastic and Reconstructive Surgery, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea
Abstract:
Frequent mutation of APC (90%) in advanced colorectal cancer (CRC) results in the simultaneous activation of Wnt/β-catenin and AKT signaling pathways, and the current therapeutic limitations of the AKT inhibitors for treating CRC patients are nuclear β-catenin-induced EMT and bypassing apoptosis. In this study, we discover that the combinatorial treatment of an AKT inhibitor and KY1022, a β-catenin destabilizer, effectively overcomes the current limitations of API-2, an AKT inhibitor, by reducing nuclear β-catenin. Taken together, we demonstrate that the simultaneous suppression of Wnt/β-catenin with the AKT signaling pathways is an ideal strategy for suppressing the AKT-inhibitor-mediated metastasis and for maximizing the therapeutic effects of AKT inhibitors.
Keywords:colorectal cancer, cell migration, EMT, resistance to AKT inhibitor, Wnt/β  -catenin pathway, PI3K-AKT pathway, FOXO3a
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