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Inhibition of cellular proliferation by the genistein metabolite 5,7,3',4'-tetrahydroxyisoflavone is mediated by DNA damage and activation of the ATR signalling pathway

Vauzour, D., Vafeiadou, K., Rice-Evans, C., Cadenas, E. and Spencer, J. P. E. (2007) Inhibition of cellular proliferation by the genistein metabolite 5,7,3',4'-tetrahydroxyisoflavone is mediated by DNA damage and activation of the ATR signalling pathway. Archives of Biochemistry and Biophysics, 468 (2). pp. 159-166. ISSN 0003-9861

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To link to this article DOI: 10.1016/j.abb.2007.09.021

Abstract/Summary

The cellular actions of genistein, and its in vivo metabolites, are believed to mediate the decreased risk of breast cancer associated with high soy consumption. The genistein metabolite, 5,7,3',4'-tetrahydroxyisoflavone (THIF), induced G2-M cell cycle arrest in T47D tumorigenic breast epithelial cells via a mechanism involving the activation of ataxia telangiectasia and Rad3-related kinase (ATR) via its phosphorylation at Ser(428). This activation of ATR appeared to result from THIF-induced increases in intracellular oxidative stress, a depletion of cellular GSH and an increase in DNA strand breakage. THIF treatment also led to an inhibition of cdc2, which was accompanied by the phosphorylation of both p53 (Ser(15)) and Chk1 (Ser(296)) and the de-activation of cdc25C phosphatase. We suggest the anti-proliferative actions of THIF may be mediated by initial oxidative DNA damage, activation of ATR and downstream regulation of the p53 and Chk1 pathways leading to cell cycle arrest in G2-M. This may represent one mechanism by which genistein exerts its cellular activity in vivo. (c) 2007 Elsevier Inc. All rights reserved.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > Department of Food and Nutritional Sciences
Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR)
ID Code:12898
Uncontrolled Keywords:Breast Neoplasms/*metabolism, Cell Cycle, Proteins/*metabolism, Cell Line, Tumor, Cell Proliferation/drug effects, DNA Damage/*drug effects Dose-Response Relationship, Drug, Genistein, Humans, Isoflavones/*administration & dosage, Protein-Serine-Threonine Kinases/*metabolism Signal Transduction/*drug effectsgenistein, breast cancer, metabolism, cell signalling, isoflavone, cell, cycle, p53, DNA damage, oxidative stress, mammary epithelial-cells, breast-cancer cells, in-vivo metabolites, cycle arrest, base modification, cdc25c expression, strand breakage, melanoma-cells, protein-kinase, phosphorylation
Additional Information:Research Support, Non-U.S. Gov't United States

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