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Knockdown of c-MET induced apoptosis in ABCB1-overexpressed multidrug-resistance cancer cell lines

Cancer Gene Therapy volumeĀ 22,Ā pages 262ā€“270 (2015)Cite this article

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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 PKCĪ“ 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.

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Acknowledgements

This work was supported in part by the Taiwan Ministry of Science and Technology, NSC 95-2320-B-182-028-MY3 and MOST 103-2320-B-182-021 to KYC, NSC 99-2632-B-182-001-MY3 to CPT, NSC 102-2815-C-182-062-B to YHL. The Chang Gung Memorial Hospital Grant (CMRPD 34012, CMRPD 180133, CMRPD1B0472, CMRPD1B0473) and Taiwan Ministry of Education (EMRPD1C0121). The IVIS imaging facilities were supported by the SPF Animal Center Animal Image Laboratory, Chang Gung University. The tissue slide imaging by HistoFAXS of Molecular Imaging Center, Chang Gung Memorial Hospital, Linkou Medical Center, TaoYuan. Taiwan.

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Authors and Affiliations

  1. Division of Biotechnology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Republic of China

    T-H Hung,Ā C-P Tseng,Ā Y-W Lan,Ā H-C LaiĀ &Ā K-Y Chong

  2. Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Republic of China

    Y-H Li,Ā C-P Tseng,Ā H-C LaiĀ &Ā K-Y Chong

  3. Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Republic of China

    C-P TsengĀ &Ā K-Y Chong

  4. Cancer Molecular Diagnostic Laboratory, Chang-Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Republic of China

    S-C Hsu

  5. Department of Pathology, Chang-Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Republic of China

    S-C Hsu

  6. Graduate Institute of Pharmaceutical Sciences and Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Republic of China

    Y-H Chen

  7. Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China

    T-T Huang

  8. Department of Life Sciences, National Chung Hsing University, Taichung, Republic of China

    C-M Chen

  9. Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Republic of China

    C-M Chen

  10. Rong-Hsing Translational Medicine Center, National Chung Hsing University, Taichung, Republic of China

    C-M Chen

  11. Department of Preclinical Sciences, Faculty of Medicine and Health Sciences and Centre for Stem Cell Research, Universiti Tunku Abdul Rahman, Selangor, Malaysia

    K-B Choo

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Hung, TH., Li, YH., Tseng, CP. et al. Knockdown of c-MET induced apoptosis in ABCB1-overexpressed multidrug-resistance cancer cell lines. Cancer Gene Ther 22, 262ā€“270 (2015). https://doi.org/10.1038/cgt.2015.15

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