Gentiopicroside inhibits the progression of gastric cancer through modulating EGFR/PI3K/AKT signaling pathway

Abstract

Abstract Background This study was designed to clarify the function and potential mechanism of gentiopicroside (GPS) in regulating the malignant progression of gastric cancer (GC) through in vitro cellular experiments and in vivo animal models. Methods AGS and HGC27 cells were divided into control group and GPS treatment groups (50 µM and 100 µM). Then, the cellular proliferation, colony formation, migration, invasion, and apoptosis were detected, respectively. Transmission electron microscope (TEM) was used to observe the mitochondrial changes, and the mitochondrial membrane potential (MMP) was determined using the JC-1 commercial kit. Network pharmacology analysis was utilized to screen the potential molecule that may be related to the GPS activity on GC cells, followed by validation tests using Western blot in the presence of specific activator. In addition, xenografted tumor model was established using BALB/c nude mice via subcutaneous injection of HGC27 cells, along with pulmonary metastasis model. Then, the potential effects of GPS on the tumor growth and metastasis were detected by immunohistochemistry (IHC) and HE staining. Results GPS inhibited the proliferation, invasion and migration of GC cell lines in a dose-dependent manner. Besides, it could induce mitochondrial apoptosis. Epidermal growth factor receptor (EGFR) may be a potential target for GPS action in GC by network pharmacological analysis. GPS inhibits activation of the EGFR/PI3K/AKT axis by reducing EGFR expression. In vivo experiments indicated that GPS induced significant decrease in tumor volume, and it also inhibited the pulmonary metastasis. For the safety concerns, GPS caused no obvious toxicities to the heart, liver, spleen, lung and kidney tissues. IHC staining confirmed GPS downregulated the activity of EGFR/PI3K/AKT. Conclusions Our investigation demonstrated for the first time that GPS could inhibit GC malignant progression by targeting the EGFR/PI3K/AKT signaling pathway. This study indicated that GPS may be serve as a safe anti-tumor drug for further treatment of GC.

Keywords

• Gentiopicroside
• PI3K/AKT signaling pathway
• EGFR
• Gastric cancer
• Apoptosis