Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 46, Pages 20027-20032Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1010430107
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Funding
- National Institutes of Health [CA121105, CA106348, CA129829, U01-DK085570]
- National Institute of Diabetes and Digestive and Kidney Diseases
- American Cancer Society [RSG-07-156-01-CNE, RGS-10-124-01-CCE]
- Flight Attendant Medical Research Institute
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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.
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