Protective effect of quercetin against arsenite-induced COX-2 expression by targeting PI3K in rat liver epithelial cells.
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.
Lee
Kyung Mi
KM
Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea.
Hwang
Mun Kyung
MK
Lee
Dong Eun
DE
Lee
Ki Won
KW
Lee
Hyong Joo
HJ
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D014407:Tumor Cells, Cultured
D018053:Arsenites; D011794:Quercetin; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; C015001:arsenite