Ginsenoside Rg3 induces FUT4-mediated apoptosis in H. pylori CagA-treated gastric cancer cells by regulating SP1 and HSF1 expressions

Abstract

Helicobacter pylori (H. pylori) cytotoxin associated antigen A (CagA) plays a significant role in the development of gastric cancer. Ginsenoside Rg3 is a herbal medicine which inhibits cell proliferation and induces apoptosis in various cancer cells. Fucosylation plays important roles in cancer biology as increased fucosylation levels of glycoproteins and glycolipids have been reported in many cancers. Fucosyltransferase IV (FUT4) is an essential enzyme, catalyzes the synthesis of LewisY oligosaccharides and is regulated by specificity protein 1 (SP1) and heat shock factor protein 1 (HSF1) transcription factors. Herein, we studied the mechanism action of Rg3 apoptosis induction in gastric cancer cells. We treated the gastric cancer cells with CagA followed by Rg3, and analyzed their ability to induce apoptosis by evaluating the role of FUT4 as well as SP1 and HSF1 expressions by Western blot, flow cytometry and ELISA. We found that Rg3 significantly induced apoptosis in CagA treated gastric cancer cells, as evidenced by nuclear staining of 4-6-diamidino-2-phenylindole (DAPI) and Annexin-V/PI double-labeling. In addition, Rg3 significantly increased the expression of pro-apoptotic proteins and triggered the activation of caspase-3, -8, and -9 and PARP. Moreover, Rg3-induced apoptotic mechanisms indicated that Rg3 inhibited FUT4 expression through SP1 upregulation and HSF1 downregulation. Hence, Rg3 therapy is an effective strategy for gastric cancer treatment. Furthermore SP1 and HSF1 may serve as potential diagnostic and therapeutic targets for gastric cancer.