PI3K inhibitor 3-MA promotes the antiproliferative activity of esomeprazole in gastric cancer cells by downregulating EGFR via the PI3K/FOXO3a pathway

Abstract

Gastric cancer is a common gastrointestinal malignancy worldwide, with a high mortality rate and poor prognosis. Esomeprazole (ESO) has been shown to have anticancer activity by affecting cell growth and autophagy and its mechanism in gastric cancer cells is evident. The PI3K/AKT/FOXO3a pathway is central in cancers. 3-Methyladenine (3-MA), a dual inhibitor of PI3K and autophagy, plays a synergistic role in combination with antitumor agents. In this study, we assessed the role of ESO on the PI3K/AKT/FOXO3a pathway and the beneficial effects of ESO combined with 3-MA in gastric cancer cells. Cell viability, proliferation, invasion, migration, apoptosis, autophagy, and protein expression were detected by CCK-8, EdU, Transwell, flow cytometry, immunofluorescence assay, and western blot. ESO decreased cell viability in a concentration- and time-dependent manner and increased autophagy with upregulation of LC3II and P62. Additionally, ESO inhibited the proliferation, migration, and invasion and induced the apoptosis of gastric cancer cells in a concentration-dependent manner. ESO inhibited PI3K/AKT/FOXO3a signaling and EGFR and SKP2 expression concentration-dependent. 3-MA enhanced the antiproliferative activity of ESO and synergistically inhibited PI3K/FOXO3a signaling and the expression of EGFR but not SKP2. Furthermore, pretreatment with the EGFR inhibitor AG1478 enhanced the antiproliferative activity of ESO in gastric cancer cells. In conclusion, our results suggested that the PI3K inhibitor 3-MA promotes the antiproliferative activity of ESO in gastric cancer cells by synergistically downregulating EGFR via the PI3K/FOXO3a pathway.

Keywords

• PI3K inhibitor
• Esomeprazole
• Proliferation
• Gastric cancer cells
• EGFR