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Knockdown of c-MET induced apoptosis in ABCB1-overexpressed multidrug-resistance cancer cell lines
T-H Hung1, Y-H Li2, C-P Tseng3
1Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Republic of China.
Abstract:
Inappropriate c-MET signaling in cancer can enhance tumor cell proliferation, survival, motility, and invasion. Inhibition of c-MET signaling induces apoptosis in a variety of cancers. It has also been recognized as a novel anticancer therapy approach. Furthermore, reports have also indicated that constitutive expression of P-glycoprotein (ABCB1) is involved in the HGF/c-MET-related pathway of multidrug resistance ABCB1-positive human hepatocellular carcinoma cell lines. We previously reported that elevated expression levels of PKCδ and AP-1 downstream genes, and HGF receptor (c-MET) and ABCB1, in the drug-resistant MES-SA/Dx5 cells. Moreover, leukemia cell lines overexpressing ABCB1 have also been shown to be more resistant to the tyrosine kinase inhibitor imatinib mesylate. These findings suggest that chemoresistant cancer cells may also develop a similar mechanism against chemotherapy agents. To circumvent clinical complications arising from drug resistance during cancer therapy, the present study was designed to investigate apoptosis induction in ABCB1-overexpressed cancer cells using c-MET-targeted RNA interference technology in vitro and in vivo. The results showed that cell viability decreased and apoptosis rate increased in c-MET shRNA-transfected HGF/c-MET pathway-positive MES-SA/Dx5 and MCF-7/ADR2 cell lines in a dose-dependent manner. In vivo reduction of tumor volume in mice harboring c-MET shRNA-knockdown MES-SA/Dx5 cells was clearly demonstrated. Our study demonstrated that downregulation of c-MET by shRNA-induced apoptosis in a multidrug resistance cell line.
Insights
Targeting the c-MET pathway with RNA interference effectively induces apoptosis in multidrug-resistant cancer cells. This approach shows promise for overcoming chemotherapy resistance and reducing tumor volume in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Aberrant c-MET signaling drives cancer progression, including proliferation, survival, and invasion.
- P-glycoprotein (ABCB1) expression is linked to multidrug resistance (MDR) in cancers, potentially involving the HGF/c-MET pathway.
- Elevated c-MET and ABCB1 expression correlates with drug resistance in specific cancer cell lines.
Purpose of the Study:
- To investigate the efficacy of c-MET-targeted RNA interference in inducing apoptosis in ABCB1-overexpressed, multidrug-resistant cancer cells.
- To evaluate the in vitro and in vivo effects of c-MET downregulation on cancer cell viability and tumor growth.
Main Methods:
- Utilized c-MET-targeted short hairpin RNA (shRNA) technology for gene silencing.
- Assessed apoptosis induction and cell viability in vitro in MES-SA/Dx5 and MCF-7/ADR2 cell lines.
- Evaluated tumor volume reduction in vivo in mice bearing c-MET shRNA-knockdown xenografts.
Main Results:
- c-MET shRNA transfection led to a dose-dependent decrease in cell viability and a significant increase in apoptosis rates.
- Downregulation of c-MET expression was confirmed in the treated cell lines.
- Significant reduction in tumor volume was observed in vivo in mice with c-MET shRNA-knockdown tumors.
Conclusions:
- Downregulation of c-MET via shRNA effectively induces apoptosis in multidrug-resistant cancer cells.
- c-MET-targeted RNA interference represents a potential therapeutic strategy to overcome chemotherapy resistance.
- This approach demonstrates efficacy both in vitro and in vivo, suggesting clinical relevance for treating resistant cancers.
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