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.
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.
Lee
Dong Eun
DE
The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
Lee
Ki Won
KW
Song
Nu Ry
NR
Seo
Sang Kwon
SK
Heo
Yong-Seok
YS
Kang
Nam Joo
NJ
Bode
Ann M
AM
Lee
Hyong Joo
HJ
Dong
Zigang
Z
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
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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