There is a wide range of pharmacological effects for glycyrrhetinic acid (GRA). Previous studies have shown that GRA could inhibit the proliferation of tumor cells, showing a promising value in the treatment of gastric cancer (GC). Nonetheless, the precise mechanism of the effect of GRA on GC remains unclear. We explored cellular and molecular mechanisms of GRA based on network pharmacology and in vitro experimental validation. In this study, we predicted 156 potential therapeutic targets for GC with GRA from public databases. We then screened the hub targets using protein-protein interaction network (PPI) and conducted clinical correlation analysis. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment showed that GRA made anti-GC effects through multiple targets and pathways, particularly the MAPK signaling pathway. Next, molecular docking results revealed a potential interaction between GRA and MAPK3. In addition, qRT-PCR experiments revealed that 18β-GRA was able to suppress mRNA expression of KRAS, ERK1 and ERK2 in AGS cells. Western blotting results also revealed that 18β-GRA was able to suppress the expression of KRAS and p-ERK1/2 proteins in AGS cells. Additionally, immunofluorescence assays revealed that 18β-GRA inhibited p-ERK1/2 nuclear translocation in AGS cells. These results systematically reveal that 18β-GRA may have anti-tumor effects on GC by modulating the MAPK signaling pathway.
Keywords: MAPK signaling pathway; gastric cancer; glycyrrhetinic acid; molecular docking; network pharmacology.