Siva-1 regulates multidrug resistance of gastric cancer by targeting MDR1 and MRP1 via the NF-KB pathway

Abstract

Siva-1 is a well-known anti-apoptosis protein that serves a role in multiple types of cancer cells. However, whether Siva-1 affects multidrug resistance via the N F - K B pathway in gastric cancer is currently unknown. The present study aimed to determine the possible involvement of Siva-1 in gastric cancer anticancer drug resistance in vitro. A vincristine (VCr)-resistant KATO III/VCr gastric cancer cell line with stable Siva-1 overexpression was established. The protein expression levels of Siva-1, N F - K B, multidrug resistance 1 (MDr1) and multidrug resistance protein 1 (MrP1) were detected via western blotting. The effect of Siva-1 overexpression on anticancer drug resistance was assessed by measuring the 50% inhibitory concentration of KATO III/VCR cells to VCR, 5-ftuorouracil and doxorubicin. The rate of doxorubicin efflux and apoptosis were detected by flow cytometry. Additionally, colony formation, wound healing and Transwell assays were used to detect the prolifera¬ tion, migration and invasion of cells, respectively. The results of the current study revealed that the Siva-1-overexpressed KATO III/VCR gastric cancer cells exhibited a significantly decreased sensitivity to VCR, 5-fluorouracil and doxorubicin. The results of flow cytometry revealed that the percentage of apoptotic cells decreased following overexpression of Siva-1. The colony formation assay demonstrated that cell growth and proliferation were significantly promoted by Siva-1 overexpression. Additionally, Siva-1 overexpression increased the migration and invasion of KATO H I / V C R cells in vitro. Western blot analysis determined that Siva-1 overexpression increased N F - K B, M D R 1 and M R P 1 levels. The current study demonstrated that overexpression of Siva-1, which functions as a regulator of MDR1 and MRP1 gene expression in gastric cancer cells via promotion of N F - K B expression, inhibited the sensitivity of gastric cancer cells to certain chemotherapies. These data provided novel insight into the molecular mecha¬ nisms of gastric cancer, and may be of significance for the clinical diagnosis and therapy of patients with gastric cancer.