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Carcinogenesis Advance Access published online on June 23, 2005
Carcinogenesis, doi:10.1093/carcin/bgi165
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received May 2, 2005
Revised June 8, 2005
Accepted June 15, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Resveratrol causes Cdc2-tyr15 phosphorylation via ATM/ATR-Chk1/2-Cdc25C pathway as a central mechanism for S phase arrest in human ovarian carcinoma Ovcar-3 cells

Alpna Tyagi 1, Rana P. Singh 1, Chapla Agarwal 2, Sunitha Siriwardana 3, Robert A. Sclafani 3, and Rajesh Agarwal 2*

1 Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA
2 Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA; University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80262, USA
3 University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80262, USA; Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Denver, CO 80262, USA

* To whom correspondence should be addressed.
Rajesh Agarwal, E-mail: Rajesh.Agarwal{at}UCHSC.edu


  Abstract

Resveratrol is one of the most extensively studied cancer chemopreventive agents; however, its mechanisms of action are not completely understood. Here, we observed that resveratrol induces S phase arrest via Tyr15 phosphorylation of Cdc2 in human ovarian carcinoma Ovcar-3 cells. Overexpression of Cdc2AF, a mutant resistant to Thr14 and Tyr15 phosphorylation, ablated resveratrol-induced S phase arrest. Further upstream, we observed that resveratrol causes phosphorylation of Cdc25C tyrosine phosphatase via the activation of checkpoint kinases Chk1 and Chk2, which in turn were activated via ATM (Ataxia Telangiectasia Mutated)/ATR (ataxia telangiectasia-Rad3-related) kinase in response to DNA damage, as resveratrol also increased phospho-H2A.X(Ser139) that is known to be phosphorylated by ATM/ATR in response to DNA damage. The involvement of these molecules in resveratrol-induced S phase was also supported by the studies showing that addition of ATM/ATR inhibitor caffeine reverses resveratrol-caused activation of ATM/ATR-Chk1/2 as well as phosphorylation of Cdc25C, Cdc2 and H2A.X, and S phase arrest. In additional studies assessing whether observed effects of resveratrol are specific to Ovcar-3 cells, we observed that it also induces S phase arrest and H2A.X(Ser139) phosphorylation in other ovarian cancer cell lines PA-1 and SKOV3, albeit at different levels; whereas resveratrol showed only marginal S phase arrest in normal human foreskin fibroblasts with undetectable level of phospho-H2A.X(Ser139). These findings for the first time identify that resveratrol causes Cdc2-tyr15 phosphorylation via ATM/ATR-Chk1/2-Cdc25C pathway as a central mechanism for DNA damage and S phase arrest selectively in ovarian cancer cells, and provide a rationale for the potential efficacy of ATM/ATR agonists in the prevention and intervention of cancer.

Keywords: chemoprevention; resveratrol; ovarian cancer; cell cycle; Chk1/2; Cdc25C; Cdc2; H2A.X; ATM/ATR.
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