The mechanism study of lentiviral vector carrying methioninase enhances the sensitivity of drug-resistant gastric cancer cells to Cisplatin
Menée sur des lignées cellulaires de cancer gastrique résistant aux sels de cisplatine et à l'aide d'un modèle murin, cette étude met en évidence l'intérêt thérapeutique et le mécanisme d'action d'un vecteur lentiviral exprimant une méthioninase
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
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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
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Our results suggest that LV-METase has potential as a therapeutic agent for gastric cancer treatment.