title: 7,3',4'-Trihydroxyisoflavone inhibits epidermal growth factor-induced proliferation and transformation of JB6 P+ mouse epidermal cells by suppressing cyclin-dependent kinases and phosphatidylinositol 3-kinase.
abstract: Numerous in vitro and in vivo studies have shown that isoflavones exhibit anti-proliferative activity against epidermal growth factor (EGF) receptor-positive malignancies of the breast, colon, skin, and prostate. 7,3',4'-Trihydroxyisoflavone (7,3',4'-THIF) is one of the metabolites of daidzein, a well known soy isoflavone, but its chemopreventive activity and the underlying molecular mechanisms are poorly understood. In this study, 7,3',4'-THIF prevented EGF-induced neoplastic transformation and proliferation of JB6 P+ mouse epidermal cells. It significantly blocked cell cycle progression of EGF-stimulated cells at the G(1) phase. As shown by Western blot, 7,3',4'-THIF suppressed the phosphorylation of retinoblastoma protein at Ser-795 and Ser-807/Ser-811, which are the specific sites of phosphorylation by cyclin-dependent kinase (CDK) 4. It also inhibited the expression of G(1) phase-regulatory proteins, including cyclin D1, CDK4, cyclin E, and CDK2. In addition to regulating the expression of cell cycle-regulatory proteins, 7,3',4'-THIF bound to CDK4 and CDK2 and strongly inhibited their kinase activities. It also bound to phosphatidylinositol 3-kinase (PI3K), strongly inhibiting its kinase activity and thereby suppressing the Akt/GSK-3beta/AP-1 pathway and subsequently attenuating the expression of cyclin D1. Collectively, these results suggest that CDKs and PI3K are the primary molecular targets of 7,3',4'-THIF in the suppression of EGF-induced cell proliferation. These insights into the biological actions of 7,3',4'-THIF provide a molecular basis for the possible development of new chemoprotective agents.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
authors.forename: Dong Eun
authors.initials: DE
authors.lastname: Lee
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Nu Ry
authors.initials: NR
authors.lastname: Song
authors.forename: Sang Kwon
authors.initials: SK
authors.lastname: Seo
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Heo
authors.forename: Nam Joo
authors.initials: NJ
authors.lastname: Kang
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D012878:Skin Neoplasms / Q000188:drug therapy / Q000517:prevention & control
chemical_list: D016588:Anticarcinogenic Agents; D007529:Isoflavones; D016160:Retinoblastoma Protein; D012694:Serine; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D018844:Cyclin-Dependent Kinases; C061213:3',4',7-trihydroxyisoflavone
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