| 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. | |
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MedLine Citation:
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PMID: 21268136 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Manjinder Kaur; Alpna Tyagi; Rana P Singh; Robert A Sclafani; Rajesh Agarwal; Chapla Agarwal |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-01-25 |
Journal Detail:
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Title: Molecular carcinogenesis Volume: 50 ISSN: 1098-2744 ISO Abbreviation: Mol. Carcinog. Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-06-07 Completed Date: 2011-08-01 Revised Date: 2012-09-24 |
Medline Journal Info:
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Nlm Unique ID: 8811105 Medline TA: Mol Carcinog Country: United States |
Other Details:
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Languages: eng Pagination: 553-62 Citation Subset: IM |
Copyright Information:
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Copyright © 2011 Wiley-Liss, Inc. |
Affiliation:
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Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Aurora, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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 Humans Mitogen-Activated Protein Kinase 1 / metabolism* Mitogen-Activated Protein Kinase 3 / metabolism* Oxidation-Reduction Polymerase Chain Reaction RNA Processing, Post-Transcriptional* Up-Regulation / drug effects* |
| Grant Support | |
ID/Acronym/Agency:
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R01 AT003623-04/AT/NCCAM NIH HHS; R01 AT003623-05/AT/NCCAM NIH HHS; R01AT003623/AT/NCCAM NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/DNA Primers; 0/Grape Seed Extract; EC 2.7.11.24/MAPK1 protein, human; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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