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Extracellular acidity has been implicated in enhanced malignancy and metastatic features in various cancer cells. Gastric cancer cell lines (AGS and SNU601) maintained in an acidic medium have increased motility and invasiveness. In this study, we investigated the effect of ellagic acid, a plant-derived phenolic compound, on the acidity-promoted migration and invasion of gastric cancer cells. Treating cells maintained in acidic medium with ellagic acid inhibited acidity-mediated migration and invasion, and reduced the expression of MMP7 and MMP9. Examining regulatory factors contributing to the acidity-mediated invasiveness, we found that an acidic pH increased the expression of COX1 and COX2; importantly, expression decreased under the ellagic acid treatment. The general COX inhibitor, sulindac, also decreased acidity-mediated invasion and expression of MMP7 and MMP9. In addition, acidity increased the mRNA protein expression of transcription factors snail, twist1, and c-myc; these were also reduced by ellagic acid. Together, these results suggest that ellagic acid suppresses acidity-enhanced migration and invasion of gastric cancer cells via inhibition of the expression of multiple factors (COX1, COX2, snail, twist1, and c-myc); for this reason, it may be an effective agent for cancer treatment under acidosis.

Ellagic Acid Inhibits Extracellular Acidity-Induced Invasiveness and Expression of COX1, COX2, Snail, Twist 1, and c-myc in Gastric Carcinoma Cells