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

Wei Qiu, Xinwei Wang, Brian Leibowitz, Hongtao Liu, Nick Barker, Hitoshi Okada, Naohide Oue, Wataru Yasui, Hans Clevers, Robert E. Schoen, Jian Yu, Lin Zhang

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

86 Citaten (Scopus)

Samenvatting

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 apopto- sis to remove the intestinal stem cells with nuclear or phosphorylated β-catenin in APCMin/+ 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 p-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.

Originele taal-2Engels
Pagina's (van-tot)20027-20032
Aantal pagina's6
TijdschriftProceedings of the National Academy of Sciences of the United States of America
Volume107
Nummer van het tijdschrift46
DOI's
StatusGepubliceerd - 16 nov. 2010
Extern gepubliceerdJa

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