Abstract
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.
- Received February 6, 2025.
- Revision received February 24, 2025.
- Accepted March 10, 2025.
- Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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