Knockdown of c-Met inhibits cell proliferation and invasion and increases chemosensitivity to doxorubicin in human multiple myeloma U266 cells in vitro

Abstract

Abstract. c-Met, a receptor tyrosine kinase and its ligand, hepatocyte growth factor, are critical in cellular proliferation, motility and invasion and confer resistance to specific chemotherapeutic drugs. However, little is known about the impact of c-Met knockdown on the biological functions of human multiple myeloma u266 cells. The present study was designed to determine the role of c-Met in the proliferation and invasion of u266 cells, using rna interference technology in vitro. in our study, the c-Met short hairpin rna (shrna) was successfully transfected into u266 cells, which resulted in the significant inhibition of transcription and expression of c-Met. The down-regulation of c-Met inhibited the proliferation potential, adherence and invasiveness of u266 cells, and also increased chemosensitivity to doxorubicin. The c-Met shRNA in u266 cells induced apoptosis and increased the accumulation of cleavage ParP and cleavage caspase-3. However, the expression of Bcl-2 and Bax did not change following the c-Met knockdown. Taken together, our data reveal that the down-regulation of c-Met inhibits proliferation and invasion and increases the chemosensitivity of u266 cells. Thus, the targeting of c-Met could be an effective therapeutic approach against multiple myeloma. IntroductionMultiple myeloma (MM) is the second most common hematological malignancy, characterized by the clonal proliferation of neoplastic plasma cells in the bone marrow (BM). At present, MM is an incurable disease, in spite of the fact that most patients to a certain extent respond to chemotherapy. High-dose chemotherapy with stem cell support has achieved higher response rates than conventional therapies, but few patients remain in long-term remission. new effective anticancer targets for both early and advanced MM is a dynamic research area (1-5).The interaction of MM cells with extracellular matrix (ECM) proteins and BM cells, as well as factors in the BM milieu (cytokines, chemokines and angiogenesis), play a crucial role in MM pathogenesis (6-9). The interaction of MM cells with the BM microenvironment activates MM cell proliferation and the anti-apoptotic signaling cascades (10,11). These molecular events are triggered directly, via cell adhesion molecule-mediated interactions, or indirectly by growth factors released by BM stromal cells (BMSCs), MM cells or both (12,13).Hepatocyte growth factor (HGF) is a multifunctional protein. c-Met is the receptor for HGF, a protein product of a proto-oncogene (14). it is a transmembrane tyrosine kinase with structural and functional features of a growth factor receptor (15). on binding with its ligand, autophosphorylation of the receptor stimulates its intrinsic tyrosine kinase activity with resultant changes in cellular motility, growth and invasion. c-Met overexpression has been found in numerous human tumors (16,17). Previous studies have revealed that c-Met and its ligand HGF are overexpressed in human myeloma cell lines (JJn-3, u-266, oH-2 and JW) and primary human MM cells (18). in addition,...

Quercetin reverses the doxorubicin resistance of prostate cancer cells by downregulating the expression of c‑met

“…For example, activation of the c-met pathway triggered the expression of focal adhesion kinase and downregulated apoptosis-inducing factor expression to develop cisplatin resistance in lung cancer ( 23 ). In human multiple myeloma, c-met knockdown resulted in decreased drug-resistance and increased chemosensitivity to doxorubicin ( 24 ). Therefore, the inhibition of c-met and its downstream signaling targets has been considered as a potential strategy to enhance the therapeutic efficacy for the treatment of cancer ( 25 , 26 ).…”

Liposarcoma: molecular targets and therapeutic implications

“…Tyrosine kinase receptors have been utilized as key targets for molecular based therapies due to their direct impact on signaling pathways. Aberrant activation of the Met pathway has been implicated in multiple tumor types, including sarcoma [43][44][45][46][47], and combination treatment with standard chemotherapy has been demonstrated to be effective against proliferation in multiple myeloma [48]. In LPS, increased Met pathway activation has been observed [49].…”

Discovery of an Indirubin Derivative as a Novel c-Met Kinase Inhibitor with In Vitro Anti-Tumor Effects

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