Abstract
BackgroundTo investigate the mechanism of lentiviral vector carrying methioninase enhances the sensitivity of drug-resistant gastric cancer cells to Cisplatin.MethodsDeath 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.ResultsThe 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.ConclusionsOur results suggest that LV-METase has potential as a therapeutic agent for gastric cancer treatment.
Highlights
The progress of medical technology has been made to improve gastric cancer outcomes, stomach cancer is still the fourth most common malignancies in the world
The cell apoptosis of SGC7901, SGC7901/ DDP, BGC823, and BGC823/DDP was increased in a concentrationdependent manner of Cisplatin, while the cell apoptosis showed no significant difference between resistant cells and control (Cisplatin concentration = 0) when the Cisplatin concentration reached to 1 μg/ml (Supplementary Figure 1C)
We found that LV-METase enhances cell death in Cisplatin-stimulated conditions by a mechanism involving the inhibition of nuclear factor-κB (NF-κB)/miR-21 pathway and the activation of Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway (Fig. 8d)
Summary
The progress of medical technology has been made to improve gastric cancer outcomes, stomach cancer is still the fourth most common malignancies in the world. To investigate the mechanism of lentiviral vector carrying methioninase enhances the sensitivity of drug-resistant gastric cancer cells to Cisplatin. 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. 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. MiR-21 regulated by NF-κB mediated the expression of P-gp protein via inhibiting caspase-8, regulating Cisplatin-induced cell death. CONCLUSIONS: Our results suggest that LV-METase has potential as a therapeutic agent for gastric cancer treatment
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