Document Detail


The intracellular genistein metabolite 5,7,3',4'-tetrahydroxyisoflavone mediates G2-M cell cycle arrest in cancer cells via modulation of the p38 signaling pathway.
MedLine Citation:
PMID:  17015169     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The cellular actions of genistein are believed to mediate the decreased risk of breast cancer associated with high soy consumption. We have investigated the intracellular metabolism of genistein in T47D tumorigenic and MCF-10A nontumorigenic cells and assessed the cellular actions of resultant metabolites. Genistein selectively induced growth arrest and G2-M phase cell cycle block in T47D but not MCF10A breast epithelial cells. These antiproliferative effects were paralleled by significant differences in the association of genistein to cells and in particular its intracellular metabolism. Genistein was selectively taken up into T47D cells and was subject to metabolism by CYP450 enzymes leading to the formation of both 5,7,3',4'-tetrahydroxyisoflavone (THIF) and two glutathionyl conjugates of THIF. THIF inhibited cdc2 activation via the phosphorylation of p38 MAP kinase, suggesting that this species may mediate genistein's cellular actions. THIF exposure activated p38 and caused subsequent inhibition of cyclin B1 (Ser 147) and cdc2 (Thr 161) phosphorylation, two events critical for the correct functioning of the cdc2-cyclin B1 complex. We suggest that the formation of THIF may mediate the cellular actions of genistein in tumorigenic breast epithelial cells via the activation of signaling through p38.
Authors:
Dominique T Nguyen; Eva Hernandez-Montes; David Vauzour; Axel H Schönthal; Catherine Rice-Evans; Enrique Cadenas; Jeremy P E Spencer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2006-07-15
Journal Detail:
Title:  Free radical biology & medicine     Volume:  41     ISSN:  0891-5849     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  2006 Oct 
Date Detail:
Created Date:  2006-10-03     Completed Date:  2006-11-20     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1225-39     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Breast / cytology,  drug effects,  metabolism
Breast Neoplasms / drug therapy*,  metabolism,  pathology*
CDC2 Protein Kinase / metabolism
Cell Cycle / drug effects*
Cell Division / drug effects
Cell Line
Cell Line, Tumor
Cimetidine / pharmacology
Epithelial Cells / cytology,  drug effects,  metabolism
Female
G2 Phase / drug effects
Genistein / metabolism,  pharmacology*
Humans
Models, Biological
Signal Transduction / drug effects
p38 Mitogen-Activated Protein Kinases / metabolism*
Grant Support
ID/Acronym/Agency:
AG016718/AG/NIA NIH HHS; G0400278//Medical Research Council
Chemical
Reg. No./Substance:
80061L1WGD/Cimetidine; DH2M523P0H/Genistein; EC 2.7.11.22/CDC2 Protein Kinase; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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