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
Language: 
English
Abstract: 

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.

Author(s): 
Kaur, Manjinder
Tyagi, Alpna
Singh, Rana P.
Sclafani, Robert A.
Agarwal, Rajesh
Agarwal, Chapla
Item Type: 
Journal Article
Publication Title: 
Molecular Carcinogenesis
Journal Abbreviation: 
Mol. Carcinog.
Publication Date: 
Jul 2011
Publication Year: 
2011
Pages: 
553-562
Volume: 
50
Issue: 
7
ISSN: 
1098-2744
DOI: 
10.1002/mc.20739
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 21268136 PMCID: PMC3110540

Turabian/Chicago Citation

Manjinder Kaur, Alpna Tyagi, Rana P. Singh, Robert A. Sclafani, Rajesh Agarwal and Chapla Agarwal. Jul 2011. "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." Molecular Carcinogenesis 50: 7: 553-562. 10.1002/mc.20739.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1002/mc.20739 | issn = 1098-2744 | volume = 50 | pages = 553-562 | last = Kaur | first = Manjinder | coauthors = Tyagi, Alpna, Singh, Rana P., Sclafani, Robert A., Agarwal, Rajesh, Agarwal, Chapla | title = 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 | journal = Molecular Carcinogenesis | date = Jul 2011 | pmid = | pmc = }} </ref>