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.

Novel Targeting of Phospho-cMET Overcomes Drug Resistance and Induces Antitumor Activity in Multiple Myeloma

“…It has been previously shown that cMET knockdown by siRNA in U266 multiple myeloma cells increases sensitivity to both bortezomib and doxorubicin (35,36). We thus wondered whether p-cMET inhibition by SU11274 might revert the resistance to bortezomib, melphalan, and doxorubicin in R5 cells: SU11274 in combination with both bortezomib and doxorubicin successfully targeted these cells in a synergistic way [combination index (CI) < 1; isobologram analysis; Fig.…”

Blocking MET receptor signaling in multiple myeloma cells in vitro and in vivo

“…28 Que et al revealed that the down-regulation of MET inhibits the proliferation and invasion of U266 myeloma cells, and increases their chemosensitivity to doxorubicin and bortezomib. [29][30][31] Posttranscriptional gene silencing, a technique that is based on the phenomenon of RNA interference (RNAi) through siRNA, uses the natural process of gene expression dependent on double-stranded RNA. Translation of the mRNA is blocked by the introduction of siRNA with a sequence complementary to the target RNA.…”

Knockdown of DEPTOR inhibits cell proliferation and increases chemosensitivity to melphalan in human multiple myeloma RPMI-8226 cells via inhibiting PI3K/AKT activity

“…The PI3K/AKT signalling pathway plays an important role in cellular proliferation, motility, apoptosis, drug resistance and survival. 6,15,18,19 Constitutive activation of the PI3K/AKT pathway is considered to be an important molecular event that contributes to the malignant phenotype of the tumour cell in multiple myeloma. 20 The major upstream regulator of AKT is PI3K, which is activated by a variety of transmembrane receptors.…”