Document Detail

Grape seed extract upregulates p21 (Cip1) through redox-mediated activation of ERK1/2 and posttranscriptional regulation leading to cell cycle arrest in colon carcinoma HT29 cells.
MedLine Citation:
PMID:  21268136     Owner:  NLM     Status:  MEDLINE    
Abnormalities in cell cycle progression provide unlimited replicative potential to cancer cells, and therefore targeting of key cell cycle regulators could be a sound cancer chemopreventive strategy. Earlier, we found that grape seed extract (GSE) increases Cip/p21 protein level and inhibits growth and induces apoptosis in human colon carcinoma HT29 cells both in vitro and in vivo. However, the mechanism of GSE-induced p21 upregulation and its role in biological efficacy of GSE are not known, which were investigated here. GSE treatment of HT29 cells resulted in a strong dose- and time-dependent phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), consistent with p21 induction. The inhibition of sustained ERK1/2 activation by GSE using pharmacological inhibitors abrogated GSE-induced p21 upregulation. Furthermore, pretreatment of cells with N-acetylcysteine inhibited GSE-induced ERK1/2 phosphorylation as well as p21 upregulation, suggesting the involvement of GSE-induced oxidative stress as an upstream event. Consistent with this, GSE also decreased intracellular level of reduced glutathione. Next, we determined whether GSE-induced signaling regulates p21 expression at transcriptional and/or translational levels. GSE was found to increase the stability of p21 message with resultant increase in p21 protein level, but it did not alter the protein stability to a great extent. Importantly, knock-down of p21 abrogated GSE-induced G(1) arrest suggesting that p21 induction by GSE is essential for its G(1) arrest effect. Together, our results for the first time identify a central role of p21 induction and associated mechanism in GSE-induced cell cycle arrest in HT29 cells.
Manjinder Kaur; Alpna Tyagi; Rana P Singh; Robert A Sclafani; Rajesh Agarwal; Chapla Agarwal
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-01-25
Journal Detail:
Title:  Molecular carcinogenesis     Volume:  50     ISSN:  1098-2744     ISO Abbreviation:  Mol. Carcinog.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-07     Completed Date:  2011-08-01     Revised Date:  2014-09-11    
Medline Journal Info:
Nlm Unique ID:  8811105     Medline TA:  Mol Carcinog     Country:  United States    
Other Details:
Languages:  eng     Pagination:  553-62     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Wiley-Liss, Inc.
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MeSH Terms
Base Sequence
Blotting, Western
Cell Cycle / drug effects*
Colonic Neoplasms / enzymology,  metabolism*,  pathology
Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
DNA Primers
Enzyme Activation
Grape Seed Extract / pharmacology*
HT29 Cells
Mitogen-Activated Protein Kinase 1 / metabolism*
Mitogen-Activated Protein Kinase 3 / metabolism*
Polymerase Chain Reaction
RNA Processing, Post-Transcriptional*
Up-Regulation / drug effects*
Grant Support
Reg. No./Substance:
0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/DNA Primers; 0/Grape Seed Extract; EC protein, human; EC Protein Kinase 1; EC Protein Kinase 3

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