title: Genistein inhibits phorbol ester-induced NF-κB transcriptional activity and COX-2 expression by blocking the phosphorylation of p65/RelA in human mammary epithelial cells.
abstract: Genistein, an isoflavone present in soy products, has chemopreventive effects on mammary carcinogenesis. In the present study, we have investigated the effects of genistein on phorbol ester-induced expression of cyclooxygenase-2 (COX-2) that plays an important role in the pathophysiology of inflammation-associated carcinogenesis. Pretreatment of cultured human breast epithelial (MCF10A) cells with genistein reduced COX-2 expression induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). There are multiple lines of evidence supporting that the induction of COX-2 is regulated by the eukaryotic transcription factor NF-κB. Genistein failed to inhibit TPA-induced nuclear translocation and DNA binding of NF-κB as well as degradation of IκB. However, genistein abrogated the TPA-induced transcriptional activity of NF-κB as determined by the luciferase reporter gene assay. Genistein inhibited phosphorylation of the p65 subunit of NF-κB and its interaction with cAMP regulatory element-binding protein-binding protein (CBP)/p300 and TATA-binding protein (TBP). TPA-induced NF-κB phosphorylation was abolished by pharmacological inhibition of extracellular signal-regulated kinase (ERK). Likewise, pharmacologic inhibition or dominant negative mutation of ERK suppressed phosphorylation of p65. The above findings, taken together, suggest that genistein inhibits TPA-induced COX-2 expression in MCF10A cells by blocking ERK-mediated phosphorylation of p65 and its subsequent interaction with CBP and TBP.
authors.affiliation: Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Myung-Hoon
authors.initials: MH
authors.lastname: Chung
authors.affiliation: Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Do-Hee
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Food and Nutrition, Sungshin Women's University, Seoul, South Korea.
authors.forename: Hye-Kyung
authors.initials: HK
authors.lastname: Na
authors.affiliation: Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Ha-Na
authors.initials: HN
authors.lastname: Kim
authors.affiliation: LEGEST, University of Gent, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Haegeman
authors.affiliation: Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul, South Korea; Cancer Research Institute, Seoul National University, Seoul, South Korea. Electronic address: surh@snu.ac.kr.
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D050882:CREB-Binding Protein; D002273:Carcinogens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D042361:Mammary Glands, Human; D009154:Mutation; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; C498143:RELA protein, human; D051996:Transcription Factor RelA; D019833:Genistein; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D013755:Tetradecanoylphorbol Acetate
keywords: Chemoprevention; Cyclooxygenase-2; Genistein; MCF10A cells; NF-κB