Betulinic acid targets drug-resistant human gastric cancer cells by inducing autophagic cell death, suppresses cell migration and invasion, and modulates the ERK/MEK signaling pathway.

Abstract

The main purpose of this study was to examine the anticancer effects of betulinic acid - a plant triterpene, against gastric cancer, along with demonstrating its underlying mechanism. The MTT assay and clonogenic assays were executed to assess cellular viability in control and betulinic acid treated cells. Transmission electron microscopy and western blotting were implemented to study autophagy stimulation by betulinic acid. The ERK/MEK signaling pathway was monitored by western blotting. Migration and invasion of SGC-7901 cells was investigated via transwell chamber assay. Results of this investigation indicated that betulinic acid induced remarkable cytotoxicity against gastric cancer SGC-7901 cells, in contrast to normal gastric GES-1 cells. The cytotoxicity of betulinic acid was observed due to its autophagy stimulation tendency in target cells. Autophagic cell death was supported by the data attained from western blotting showing enhanced LC3-II, and lowered LC3-I and p62 expressions. Moreover, betulinic acid was observed to block the ERK/MEK signaling pathway in SGC-7901 cells, which was associated with declined levels of expressions of the phosphorylated ERK and MEK proteins. Finally, the transwell chamber assay revealed a potential lowering of migration and invasion by betulinic acid in the SGC-7901 cells. In conclusion, these results demonstrated that betulinic acid exhibited significant anti-gastric cancer effects mediated via autophagy induction, blocking of ERK/MEK signaling and suppression of migration and invasion. Therefore, betulinic acid may prove as a lead molecule in gastric cancer management and research.