Caffeic Acid Phenethyl Ester Inhibits Metastatic Properties of Acid-adapted Gastric Cancer Cells

BACKGROUND/AIM: The acidic tumor microenvironment promotes cancer invasiveness, epithelial-mesenchymal transition, and therapeutic resistance. This study aimed to investigate the long-term effects of acidic adaptation on gastric cancer cells and evaluate the anticancer properties of caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) in this context. MATERIALS AND METHODS: SNU601 gastric cancer cells were cultured in prolonged acidic conditions (pH 6.7) to establish an acid-adapted subline (SNU601-6.7). Invasion assays and qPCR were used to assess invasive potential and the expression of matrix metalloproteinases (MMPs). The effects of CA and CAPE on viability, apoptosis, invasion, and β-catenin expression were evaluated. RESULTS: SNU601-6.7 cells exhibited increased invasiveness, along with upregulation of MMP2, MMP7, and MMP9. Both CA and CAPE reduced cell viability and invasion, with CAPE exerting a significantly stronger effect and inducing moderate apoptosis. Mechanistic studies revealed that CAPE decreased total and nuclear β-catenin levels, and inhibited AKT and GSK3β phosphorylation. Further, pharmacological inhibition of AKT pathway confirmed its role in β-catenin accumulation and cell invasiveness. CONCLUSION: These findings identify CAPE as a potent inhibitor of invasion in acid-adapted gastric cancer cells by targeting the AKT/β-catenin pathway, highlighting its potential as a therapeutic candidate for gastric cancer in acidic tumor microenvironments.