Journal
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
Volume 58, Issue 9, Pages 5815-5820Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jf903698s
Keywords
Arsenite; cyclooxygenase-2; phosphatidylinositol 3-kinase; quercetin
Funding
- Basic Research Program [2009-0059628]
- World Class University Program [R31-2008-00-10056-0]
- Priority Research Centers Program [2009-0093824]
- National Research Foundation of Korea
- Ministry of Education, Science, and Technology
- BioGreen 21 Program [20070301-034-027]
- Rural Development Administration, Republic of Korea
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Abnormal expression of cyclooxygenase-2 (COX-2) and prostaglandin (PG)E(2) 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 PGE(2) 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 PGE(2) production was investigated. Pretreatment with quercetin resulted in the reduction of arsenite-induced expression of COX-2 and production of PGE(2). 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 PGE(2) 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.
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