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Carcinogenesis Advance Access published online on May 17, 2007
Carcinogenesis, doi:10.1093/carcin/bgm101
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Aspirin blocks Proliferation in Colon Cells by inducing a G1-Arrest and Apoptosis through Activation of the Checkpoint Kinase ATM

M. Gloria Luciani, Christoph Campregher and Christoph Gasche

Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria

Correspondence: Dr. Christoph Gasche, MUW Wien, KIM4, Div. Gastroenterology & Hepatology, Währinger Gürtel 18, A-1090 Vienna, Austria; +43-1-404004764, fax +43-1-404004735, christoph.gasche{at}meduniwien.ac.at

Colorectal cancer is the most common gastrointestinal malignancy. Most of the clinical data on colorectal cancer prevention have come from the use of aspirin. Besides inhibition of cyclooxygenases, aspirin has a diversity of molecular effects that counteract colon carcinogenesis. Aspirin restrains cell proliferation by inducing a G1 arrest in colorectal cells. To determine which cell cycle checkpoint pathways are involved in this response, colorectal cell lines wild-type or defective for p53 and p21Waf1/Cip1 were treated with aspirin or the anti-proliferative drug sulindac sulfide, then assayed for proliferative activity, for cell cycle progression and apoptosis, for the activation and phosphorylation of checkpoint components, and for the transcriptional up-regulation of p21Waf1/Cip1 and Bax. Aspirin and sulindac sulfide induced a G1-arrest within 48 hours. While all cell lines responded in a comparable way to sulindac sulfide, the aspirin-induced G1-arrest was dependent on p21Waf1/Cip1- as cells lacking the CDK inhibitor failed to show this arrest – and on ATM – as the inhibitor caffeine abrogated the checkpoint. Moreover, aspirin induced cell death mainly in cells expressing p53. Aspirin induced the phosphorylation of p53 at residue Ser15 within 8 hours in a caffeine-dependent manner, and also caused the activation of Chk2 and the cleavage of caspase 7. Our results suggest that aspirin induces a G1-arrest and apoptosis by activating p53 and p21Waf1/Cip1 in an ATM-dependent way. By activating these checkpoint pathways, aspirin may restrain uncontrolled proliferation of colorectal cells, enhance their response to stresses such as DNA damage, and promote entry of abnormal cells into apoptosis.

Key Words: Colorectal cancer • aspirin • cell cycle checkpoints • apoptosis • ATM • p21Waf1/Cip1

Received December 18, 2006; revised March 19, 2007; accepted April 17, 2007.


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