title: Quercetin suppresses cyclooxygenase-2 expression and angiogenesis through inactivation of P300 signaling.
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/EBPβ and NF-κB 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-κB. Treatment of cells with p300 HAT inhibitor roscovitine was as effective as quercetin at inhibiting p300 HAT activity. Addition of quercetin to roscovitine-treated cells did not change the roscovitine-induced inhibition of p300 HAT activity. Conversely, gene delivery of constitutively active p300 significantly reversed the quercetin-mediated inhibition of endogenous HAT activity. These results indicate that quercetin suppresses COX-2 expression by inhibiting the p300 signaling and blocking the binding of multiple transactivators to COX-2 promoter. Our findings therefore reveal a novel mechanism of action of quercetin and suggest a potential use for quercetin in the treatment of COX-2-mediated diseases such as breast cancers.
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Xiao
authors.forename: Dingbo
authors.initials: D
authors.lastname: Shi
authors.forename: Liqun
authors.initials: L
authors.lastname: Liu
authors.forename: Jingshu
authors.initials: J
authors.lastname: Wang
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xie
authors.forename: Tiebang
authors.initials: T
authors.lastname: Kang
authors.forename: Wuguo
authors.initials: W
authors.lastname: Deng
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D015345:Oligonucleotide Probes / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D011794:Quercetin / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077546:Roscovitine; D015398:Signal Transduction / Q000187:drug effects*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D000975:Antioxidants; D022782:CCAAT-Enhancer-Binding Protein-beta; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D016328:NF-kappa B; D015345:Oligonucleotide Probes; D011687:Purines; D011794:Quercetin; D000077546:Roscovitine; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor