title: Knockdown of c-Met enhances sensitivity to bortezomib in human multiple myeloma U266 cells via inhibiting Akt/mTOR activity.
abstract: The c-Met is a receptor tyrosine kinase that is overexpressed in human myeloma cell lines and promotes the survival and drug resistance of myeloma cells. This study aimed to elucidate the mechanisms by which c-Met contributes to the chemoresistance in myeloma. Stable U266 cell line in which c-Met was effectively knockdown was employed and treated with bortezomib. Cytotoxicity was evaluated by MTT assay. Cell cycle profile and apoptosis were examined by cytometry analysis. The expression of cell cycle related proteins, and the activities of caspases and Akt/mTOR were detected by Western blot analysis. The c-Met knockdown in U266 cells decreased the average IC(50) of bortezomib, induced G0/G1 phase arrest, and increased caspase-mediated apoptosis in U266 cells exposed to bortezomib. In addition, c-Met knockdown decreased the level of cyclin D1 and increased the levels of p27 and cleaved caspase 3 and caspase 9. Moreover, the Akt/mTOR activity in U266 cells treated with bortezomib was downregulated upon c-Met knockdown and c-Met knockdown U266 cells recovered chemoresistance upon the overexpression of Akt and mTOR. Our data demonstrate that c-Met is a potential therapeutic target for multiple myeloma, and Akt/mTOR is a key signaling component through which c-Met protects multiple myeloma cells from chemotherapy-induced growth inhibition and apoptosis.
authors.affiliation: Department of Hematology and Rheumatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Que
authors.forename: Junmin
authors.initials: J
authors.lastname: Chen
authors.forename: Ma
authors.initials: M
authors.lastname: Chuang
authors.forename: Danrong
authors.initials: D
authors.lastname: Jiang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; C546842:MTOR protein, human; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases