title: Rutin inhibits B[a]PDE-induced cyclooxygenase-2 expression by targeting EGFR kinase activity.
abstract: Rutin is a well-known flavonoid that exists in various natural sources. Accumulative studies have represented the biological effects of rutin, such as anti-oxidative and anti-inflammatory effects. However, the underlying mechanisms of rutin and its direct targets are not understood. We investigated whether rutin reduced B[a]PDE-induced-COX-2 expression. The transactivation of AP-1 and NF-κB were inhibited by rutin. Rutin also attenuated B[a]PDE-induced Raf/MEK/ERK and Akt activation, but had no effect on the phosphorylation of EGFR. An in vitro kinase assay revealed rutin suppressed EGFR kinase activity. We also confirmed direct binding between rutin and EGFR, and found that the binding was regressed by ATP. The EGFR inhibitor also inhibited the B[a]PDE-induced MEK/ERK and Akt signaling pathways and subsequently, suppressed COX-2 expression and promoter activity, in addition to suppressing the transactivation of AP-1 and NF-κB. In EGFR(-/-)mouse embryonic fibroblast cells, B[a]PDE-induced COX-2 expression was also diminished. Collectively, rutin inhibits B[a]PDE-induced COX-2 expression by suppressing the Raf/MEK/ERK and Akt signaling pathways. EGFR appeared to be the direct target of rutin.
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Seunghwan
authors.initials: S
authors.lastname: Choi
authors.forename: Tae-Gyu
authors.initials: TG
authors.lastname: Lim
authors.forename: Mun Kyung
authors.initials: MK
authors.lastname: Hwang
authors.forename: Yoon-A
authors.initials: YA
authors.lastname: Kim
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Kim
authors.forename: Nam Joo
authors.initials: NJ
authors.lastname: Kang
authors.forename: Tae Su
authors.initials: TS
authors.lastname: Jang
authors.forename: Jun-Seong
authors.initials: JS
authors.lastname: Park
authors.forename: Myeong Hun
authors.initials: MH
authors.lastname: Yeom
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004785:Environmental Pollutants / Q000633:toxicity*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012431:Rutin / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D048490:raf Kinases / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D004785:Environmental Pollutants; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D012431:Rutin; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Benzo[a]pyrene-7,8-diol-9,10-epoxide; Cyclooxygenase-2; EGFR; Rutin; Signaling pathway