Zeylenone Induces Mitochondrial Apoptosis and Inhibits Migration and Invasion in Gastric Cancer

Abstract

The mortality of gastric cancer (GC) is increasing due to its high rates of recurrence and metastasis. Zeylenone (Zey), a type of naturally occurring cyclohexene oxide, was demonstrated to be effective in cancer patients. The aim of this study is to explore the anti-cancer effect of Zey against gastric cancer both in vitro and in vivo, as well as the underlying mechanisms. We found that Zey inhibited gastric tumor growth, as demonstrated by in vitro gastric cancer cell lines and in a human gastric cancer xenograft mouse model. Furthermore, Zey induced substantial apoptosis through a mitochondrial apoptotic pathway, involving mitochondrial transmembrane potential loss, caspase-3 activation, anti-apoptotic protein downregulation, and pro-apoptotic protein upregulation. Notably, we revealed for the first time that Zey suppressed invasion and migration by wound healing and transwell chamber assays. Through Western blotting, we further explored the potential mechanism of Zey’s anti-cancer activity. We found that Zey downregulated the expression of matrix metalloproteinase 2/9 (MMP 2/9) and inhibited the phosphorylation of AKT and ERK. In short, Zey, which induced mitochondrial apoptosis and inhibited proliferation, migration, and invasion, may be developed as a novel drug for the treatment of gastric cancer.