Protective Effect of Quercetin against Arsenite-Induced COX-2 Expression by Targeting PI3K in Rat Liver Epithelial Cells

• Published in: Journal of agricultural and food chemistry 2010-05, Vol.58 (9), p.5815-5820
• Main Authors: Lee, Kyung Mi, Hwang, Mun Kyung, Lee, Dong Eun, Lee, Ki Won, Lee, Hyong Joo
• Format: Article
• Language: English
• Subjects: animal models; Animals; anticarcinogenic activity; arsenic; arsenite-induced COX-2 expression; arsenites; Arsenites - toxicity; Biological and medical sciences; carcinogens; Cyclooxygenase 2 - metabolism; epithelial cells; Food industries; Fundamental and applied biological sciences. Psychology; hepatocytes; liver; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - enzymology; Liver Neoplasms, Experimental - prevention & control; Molecular Nutrition; Phosphatidylinositol 3-Kinases - metabolism; prostaglandin synthase; protective effect; quercetin; Quercetin - pharmacology; Rats; Tumor Cells, Cultured
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/jf903698s

Abnormal expression of cyclooxygenase-2 (COX-2) and prostaglandin (PG)E2 is an important mediator in inflammation and tumor promotion. Arsenite is a well-known metalloid carcinogen that is strongly associated with increased risk of liver cancer, but the underlying mechanism remains to be clarified. The present study demonstrates that COX-2 expression and PGE2 secretion are up-regulated by arsenite in rat liver epithelial (RLE) cells. The possible inhibitory effect of quercetin, a naturally occurring dietary flavonol, on arsenite-induced COX-2 expression and PGE2 production was investigated. Pretreatment with quercetin resulted in the reduction of arsenite-induced expression of COX-2 and production of PGE2. The arsenite-induced phosphorylation of Akt, p70S6K, and extracellular signal-regulated protein kinases (ERKs), but not p38, was inhibited by quercetin treatment. An ex vivo kinase assay revealed that quercetin suppressed arsenite-induced phosphoinositide 3-kinase (PI3K) activity upstream of Akt in RLE cell lysates. Ex vivo pull-down assays demonstrated that quercetin directly bound with PI3K to inhibit PI3K activity. Moreover, LY294002 (a PI3K inhibitor) significantly attenuated COX-2 expression and PGE2 production in arsenite-treated RLE cells. These results suggest that quercetin suppresses arsenite-induced COX-2 expression mainly by blocking the activation of the PI3K signaling pathway, which may contribute to its chemopreventive potential.