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Knockdown of c‐Met enhances sensitivity to bortezomib in human multiple myeloma U266 cells via inhibiting Akt/mTOR activity

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Que W, Chen J, Chuang M, Jiang D. Knockdown of c‐Met enhances sensitivity to bortezomib in human multiple myeloma U266 cells via inhibiting Akt/mTOR activity. APMIS 2012; 120: 195–203.

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 IC50 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.
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Document Type: Research Article

Affiliations: 1: Department of Hematology and Rheumatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China 2: College of Pharmacy, Fujian Medical University, Fuzhou, China

Publication date: 01 March 2012

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