Inhibition of Vav3 could reverse the drug resistance of gastric cancer cells by downregulating JNK signaling pathway.

Abstract

This study aims to investigate the effect and mechanism of Vav3 on the multidrug resistance of gastric cancer. Fluorescence quantitative RT-PCR and western blot assay were used to detect Vav3 and drug resistance genes in gastric cancer tissues as well as gastric cell lines such as SGC7901, SGC7901/adriamycin (ADR) and GES-1. Besides, Vav3-specific small interfering RNA (Vav3-siRNA) was applied to inhibit Vav3 in SGC7901/ADR, and SRB assay was used to determine chemosensitivity. After that, drug resistance genes and proteins in MAPK and PI3K/AKT signaling pathway were detected after Vav3-siRNA transfection. The results showed that overexpressed Vav3 was found in gastric cancer tissues and SGC7901 and SGC7901/ADR cells. Activity of SGC7901/ADR cells transfected with Vav3-siRNA combined with 5-fluorouracil/oxaliplatin was much lower than that of control groups, and MDR1/P-gp, GST-π and Bcl-2, Bax genes were significantly downregulated in Vav3-siRNA transfection group. AKT, ERK and p38 total protein and their phosphorylation levels showed no significant change in Vav3-siRNA-transfected SGC7901/ADR cells, whereas the ratio of C-Jun phosphorylation levels to total C-Jun protein was significantly downregulated. The results suggested that Vav3 may play a role in drug resistance of gastric cancer by inhibiting drug resistance genes MDR1/P-gp, GST-π and Bcl-2 through regulating the JNK signaling pathway.