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Chemoprevention by nonsteroidal anti-inflammatory drugs eliminates oncogenic intestinal stem cells via SMAC-dependent apoptosis

Qiu, W. and Wang, X. and Leibowitz, B. and Liu, H. and Barker, N. and Okada, H. and Oue, N. and Yasui, W. and Clevers, H. and Schoen, R. E. and Yu, J. and Zhang, L. (2010) Chemoprevention by nonsteroidal anti-inflammatory drugs eliminates oncogenic intestinal stem cells via SMAC-dependent apoptosis. Proceedings of the National Academy of Sciences of the United States of America, 107, 20027-32. ISSN 0027-8424.

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Official URL: http://dx.doi.org/10.1073/pnas.1010430107

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac effectively prevent colon cancer in humans and rodent models. However, their cellular targets and underlying mechanisms have remained elusive. We found that dietary sulindac induced apoptosis to remove the intestinal stem cells with nuclear or phosphorylated beta-catenin in APC(Min/+) mice. NSAIDs also induced apoptosis in human colonic polyps and effectively removed cells with aberrant Wnt signaling. Furthermore, deficiency in SMAC, a mitochondrial apoptogenic protein, attenuated the tumor-suppressive effect of sulindac in APC(Min/+) mice by blocking apoptosis and removal of stem cells with nuclear or phosphorylated beta-catenin. These results suggest that effective chemoprevention of colon cancer by NSAIDs lies in the elimination of stem cells that are inappropriately activated by oncogenic events through induction of apoptosis.

Item Type:Article
Institutes:Hubrecht Instituut
ID Code:9456
Deposited On:04 Jan 2011 01:00
Last Modified:07 Sep 2011 17:01

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