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.
Department of Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.
Ying
Y
Dong
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.
Chao
C
Liang
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Bo
B
Zhang
Department of Internal Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.
Jianjuan
J
Ma
Department of Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.
Xuexin
X
He
Department of Oncology, Xinhua Hospital Affiliated to Medical School of Shanghai Jiaotong University, Shanghai 200092, China.
Siyu
S
Chen
Department of Cell Biology and Medical Genetics, Research Center of Molecular Medicine, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Xianning
X
Zhang
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China. Electronic address: wei_chen@zju.edu.cn.
Wei
W
Chen
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D004357:Drug Synergism; D005455:Fluorescent Antibody Technique; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C506592:APAF1 protein, human; D000970:Antineoplastic Agents; D053477:Apoptotic Protease-Activating Factor 1; D014408:Biomarkers, Tumor; D001897:Boronic Acids; D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011743:Pyrimidines; D013844:Thiazoles; D000069286:Bortezomib; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta; D000069439:Dasatinib
Bortezomib; Dasatinib; Efficacy; GISTs; Treatment; c-KIT