Siva‑1 regulates multidrug resistance of gastric cancer by targeting MDR1 and MRP1 via the NF‑κB 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 nF-κB 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, nF-κB, 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-fluorouracil 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 proliferation, 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 iii/Vcr cells in vitro. Western blot analysis determined that Siva-1 overexpression increased nF-κB, Mdr1 and MrP1 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 nF-κB expression, inhibited the sensitivity of gastric cancer cells to certain chemotherapies. These data provided novel insight into the molecular mechanisms of gastric cancer, and may be of significance for the clinical diagnosis and therapy of patients with gastric cancer.

Inhibition of apoptosis-regulatory protein Siva-1 reverses multidrug resistance in gastric cancer by targeting PCBP1

“…It is therefore urgent to design chemotherapeutics that can evade or reverse MDR. Studies have analyzed MDR1 and MRP1 gene regulation by over-expressing Siva-1 and subsequently upregulating NF-κB in gastric cancer cell lines [5]. The aim of the present study was to further clarify the influences of Siva-1 on the mechanisms of cellular resistance to chemotherapy as well as the mechanisms of action in novel potential anticancer agents, which have been designed to overcome the resistance mechanisms.…”

“…Recombinant lentiviral vector for Siva-1 gene (LV-Siva-1-RNAi) and null vector (Lv-NC), purchased from the Shanghai Cancer Institute (Shanghai, China), were used to construct the Siva-1-downregulation lentivirus. The methods of LV-Siva-1-RNAi and transfection of MKN-28/VCR gastric cancer cells with LV-Siva-1-RNAi have been previously described [5]. MKN-28/VCR cells were seeded in 6-well plates with antibiotic-free medium.…”

“…However, chemotherapy has limited efficacy due to the development of multidrug resistance (MDR). MDR leads to chemotherapy failure typically associated with a decrease in the drug concentration inside cancer cells, commonly due to MDR1 and MRP1 overexpression, which limits the efficacy of chemotherapeutic drugs [4,5].…”

“…Our previous data demonstrated that the percentage of apoptotic cells decreased following overexpression of Siva-1. Additionally, overexpression of Siva-1 functions as a regulator of MDR1 and MRP1 gene expression via promotion of NF-κB expression [5]. Siva-1 plays an important role in regulating the sensitivity of gastric cancer cells to certain chemotherapies.…”

Effects of CD133 expression on chemotherapy and drug sensitivity of adenoid cystic carcinoma

“…MDR1 and MRP1 are multi-drug resistant proteins, and their expressions can reflect the sensitivity of tumor cells to chemotherapy drugs ( 29 ). A previous study has shown that compared with CD133(−) glioblastoma stem cells, the protein expressions of MDR1 and MRP1 in CD133(+) cells are significantly increased ( 16 ).…”