The mechanism study of lentiviral vector carrying methioninase enhances the sensitivity of drug-resistant gastric cancer cells to Cisplatin
| Autor: | Chuan Liu, Lin Xin, Hou-Ting Zhang, Yi-Fan Li, Wei-Feng Yang |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death Genetic Vectors Mice Nude Antineoplastic Agents Apoptosis Article Viral vector Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Stomach Neoplasms Cell Line Tumor medicine Animals Humans Viability assay Cisplatin Mice Inbred BALB C Chemistry Lentivirus Drug Synergism Genetic Therapy Transfection Combined Modality Therapy Xenograft Model Antitumor Assays Carbon-Sulfur Lyases 030104 developmental biology Oncology Drug Resistance Neoplasm Cell culture 030220 oncology & carcinogenesis Cancer cell Cancer research Female Signal Transduction medicine.drug |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| DOI: | 10.1038/s41416-018-0043-8 |
| Popis: | Background To investigate the mechanism of lentiviral vector carrying methioninase enhances the sensitivity of drug-resistant gastric cancer cells to Cisplatin. Methods Death receptors, anti-apoptotic protein, NF-κB, and TRAIL pathway-related factors were detected. The influence of LV-METase transfection on cell viability and pathway-related proteins were assessed by MTT method and western blot, respectively. Different treatments (NF-κB or caspase-3 inhibitor induction, TRAIL supplement, etc.) were performed in gastric cancer cells and the above parameters were analysed. Moreover, the connection between miR-21 and NF-κB or caspase-8 was determined by Chip and luciferase assay, respectively. LV-METase transfection drug-resistant gastric cancer cells were injected subcutaneously into mice. Results The expression of free MET, miR-21-5p, MDR1, P-gp, and DR5 was significantly increased in drug-resistant gastric cancer cell lines. When cells were transfected with LV-METase, intracellular TRAIL signalling was activated while NF-κB pathway was inhibited. Besides, enhanced TRAIL signalling or repressed NF-κB pathway can promote the sensitivity of drug-resistant strains to Cisplatin, and the combination shows more sensitive to sensitisation. LV-METase promoted TRAIL expression by reducing NF-κB, thereby contributing to the downregulation of P-gp and enhancing the susceptibility of drug-resistant gastric cancer cells to Cisplatin. Furthermore, miR-21 regulated by NF-κB mediated the expression of P-gp protein via inhibiting caspase-8, thus regulating Cisplatin-induced cell death. Conclusions Our results suggest that LV-METase has potential as a therapeutic agent for gastric cancer treatment. |
| Databáze: | OpenAIRE |
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