quercetin suppresses cyclooxygenase-2 expression and angiogenesis through inactivation of p300 signaling槲皮素抑制cyclooxygenase-2通过失活p300信号表达和血管生成.pdfVIP

Quercetin Suppresses Cyclooxygenase-2 Expression and Angiogenesis through Inactivation of P300 Signaling 1. 1. 2. 1. 1 1 Xiangsheng Xiao , Dingbo Shi , Liqun Liu , Jingshu Wang , Xiaoming Xie , Tiebang Kang , Wuguo Deng1* 1 State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China, 2 The First Affiliated Hospital-Huangpu Hospital, Sun Yat- Sen University, Guangzhou, China Abstract Quercetin, a polyphenolic bioflavonoid, possesses multiple pharmacological actions including anti-inflammatory and antitumor properties. However, the precise action mechanisms of quercetin remain unclear. Here, we reported the regulatory actions of quercetin on cyclooxygenase-2 (COX-2), an important mediator in inflammation and tumor promotion, and revealed the underlying mechanisms. Quercetin significantly suppressed COX-2 mRNA and protein expression and prostaglandin (PG) E(2) production, as well as COX-2 promoter activation in breast cancer cells. Quercetin also significantly inhibited COX-2-mediated angiogenesis in human endothelial cells in a dose-dependent manner. The in vitro streptavidin- agarose pulldown assay and in vivo chromatin immunoprecipitation assay showed that quercetin considerably inhibited the binding of the transactivators CREB2, C-Jun, C/EBPb and NF-kB and blocked the recruitment of the coactivator p300 to COX- 2 promoter. Moreover, quercetin effectively inhibited p300 histone acetyltransferase (HAT) activity, thereby attenuating the p300-mediated acetylation of NF-kB. Treatment of cells with p300 HAT inhibitor roscovitine was as effective as quercetin at inhibiting p300 HAT activ