title: Knockdown of c-MET induced apoptosis in ABCB1-overexpressed multidrug-resistance cancer cell lines.
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.
authors.affiliation: Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Republic of China.
authors.forename: T-H
authors.initials: TH
authors.lastname: Hung
authors.affiliation: Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Republic of China.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Li
authors.affiliation: 1] Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Republic of China [2] Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Republic of China [3] Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Republic of China.
authors.forename: C-P
authors.initials: CP
authors.lastname: Tseng
authors.affiliation: Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Republic of China.
authors.forename: Y-W
authors.initials: YW
authors.lastname: Lan
authors.affiliation: 1] Cancer Molecular Diagnostic Laboratory, Chang-Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Republic of China [2] Department of Pathology, Chang-Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Republic of China.
authors.forename: S-C
authors.initials: SC
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Pharmaceutical Sciences and Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Republic of China.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
authors.forename: T-T
authors.initials: TT
authors.lastname: Huang
authors.affiliation: 1] Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Republic of China [2] Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Republic of China.
authors.forename: H-C
authors.initials: HC
authors.lastname: Lai
authors.affiliation: 1] Department of Life Sciences, National Chung Hsing University, Taichung, Republic of China [2] Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Republic of China [3] Rong-Hsing Translational Medicine Center, National Chung Hsing University, Taichung, Republic of China.
authors.forename: C-M
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Department of Preclinical Sciences, Faculty of Medicine and Health Sciences and Centre for Stem Cell Research, Universiti Tunku Abdul Rahman, Selangor, Malaysia.
authors.forename: K-B
authors.initials: KB
authors.lastname: Choo
authors.affiliation: 1] Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Republic of China [2] Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Republic of China [3] Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Republic of China.
authors.forename: K-Y
authors.initials: KY
authors.lastname: Chong
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005260:Female; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019859:Proto-Oncogene Proteins c-met / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D004317:Doxorubicin; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met