Bortezomib enhances the therapeutic efficacy of dasatinib by promoting c-KIT internalization-induced apoptosis in gastrointestinal stromal tumor cells.
Dasatinib-based therapy is often used as a second-line therapeutic strategy for imatinib-resistance gastrointestinal stromal tumors (GISTs); however, acquired aberrant activation of dasatinib target proteins, such as c-KIT and PDGFRβ, attenuates the therapeutic efficiency of dasatinib. Combination therapy which inhibits the activation of dasatinib target proteins may enhance the cytotoxicity of ... dasatinib in GISTs. Bortezomib, a proteasome inhibitor, significantly inhibited cell viability and promoted apoptosis of dasatinib-treated GIST-T1 cells, whereas GIST-T1 cells showed little dasatinib cytotoxicity when treated with dasatinib alone, as the upregulation of c-KIT caused by dasatinib itself interfered with the inhibition of c-KIT and PDGFRβ phosphorylation by dasatinib. Bortezomib induced internalization and degradation of c-KIT by binding c-KIT to Cbl, an E3 ubiquitin-protein ligase, and the subsequent release of Apaf-1, which was originally bound to the c-KIT-Hsp90β-Apaf-1 complex, induced primary apoptosis in GIST-T1 cells. Combined treatment with bortezomib plus dasatinib caused cell cycle arrest in the G1 phase through inactivation of PDGFRβ and promoted bortezomib-induced apoptosis in GIST-T1 cells. Our data suggest that combination therapy exerts better efficiency for eradicating GIST cells and may be a promising strategy for the future treatment of GISTs.
Mesh Terms:
Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Apoptotic Protease-Activating Factor 1, Biomarkers, Tumor, Blotting, Western, Boronic Acids, Bortezomib, Cell Cycle, Cell Proliferation, Dasatinib, Drug Synergism, Fluorescent Antibody Technique, Gastrointestinal Stromal Tumors, HSP90 Heat-Shock Proteins, Humans, Immunoprecipitation, Phosphorylation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-kit, Pyrazines, Pyrimidines, Receptor, Platelet-Derived Growth Factor beta, Signal Transduction, Thiazoles, Tumor Cells, Cultured
Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Apoptotic Protease-Activating Factor 1, Biomarkers, Tumor, Blotting, Western, Boronic Acids, Bortezomib, Cell Cycle, Cell Proliferation, Dasatinib, Drug Synergism, Fluorescent Antibody Technique, Gastrointestinal Stromal Tumors, HSP90 Heat-Shock Proteins, Humans, Immunoprecipitation, Phosphorylation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-kit, Pyrazines, Pyrimidines, Receptor, Platelet-Derived Growth Factor beta, Signal Transduction, Thiazoles, Tumor Cells, Cultured
Cancer Lett.
Date: May. 28, 2015
PubMed ID: 25737303
View in: Pubmed Google Scholar
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