Protective Effect of Quercetin against Arsenite-Induced COX-2 Expression by Targeting PI3K in Rat Liver Epithelial Cells
Protective Effect of Quercetin against Arsenite-Induced COX-2 Expression by Targeting PI3K in Rat Liver Epithelial Cells
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DOI：
10.1021/jf903698s
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发表时间：
2010-05-12
影响因子：
6.1
通讯作者：
Lee, Hyong Joo
中科院分区：
文献类型：
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作者：
Lee, Kyung Mi;Hwang, Mun Kyung;Lee, Hyong Joo
环氧合酶-2 (COX-2) 和前列腺素 (PG)E(2) 的异常表达是炎症和肿瘤促进的重要介质。亚砷酸盐是一种众所周知的类金属致癌物，与肝癌风险增加密切相关，但其潜在机制仍有待阐明。本研究表明，亚砷酸盐可上调大鼠肝上皮 (RLE) 细胞中 COX-2 的表达和 PGE(2) 的分泌。研究了槲皮素（一种天然膳食黄酮醇）对亚砷酸盐诱导的 COX-2 表达和 PGE(2) 产生的可能抑制作用。槲皮素预处理导致亚砷酸盐诱导的COX-2 表达和PGE(2) 产生减少。亚砷酸盐诱导的 Akt、p70S6K 和细胞外信号调节蛋白激酶 (ERK)（而非 p38）的磷酸化受到槲皮素处理的抑制。体外激酶测定表明，槲皮素可抑制 RLE 细胞裂解物中亚砷酸盐诱导的 Akt 上游磷酸肌醇 3-激酶 (PI3K) 活性。离体 Pull-down 实验表明，槲皮素直接与 PI3K 结合，抑制 PI3K 活性。此外，LY294002（一种 PI3K 抑制剂）显着减弱亚砷酸盐处理的 RLE 细胞中 COX-2 的表达和 PGE(2) 的产生。这些结果表明，槲皮素主要通过阻断 PI3K 信号通路的激活来抑制亚砷酸盐诱导的 COX-2 表达，这可能有助于其化学预防潜力。
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.