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

doi:10.1073/pnas.1010430107

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

Research output: Contribution to journal › Article › peer-review

89 Citations (Scopus)

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 apopto- sis to remove the intestinal stem cells with nuclear or phosphorylated β-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 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.

Original language	English
Pages (from-to)	20027-20032
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	107
Issue number	46
DOIs	https://doi.org/10.1073/pnas.1010430107
Publication status	Published - 16 Nov 2010
Externally published	Yes

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Qiu, W., Wang, X., Leibowitz, B., Liu, H., Barker, N., Okada, H., Oue, N., Yasui, W., Clevers, H., Schoen, R. E., Yu, J., & 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(46), 20027-20032. https://doi.org/10.1073/pnas.1010430107

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

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 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.",

author = "Wei Qiu and Xinwei Wang and Brian Leibowitz and Hongtao Liu and Nick Barker and Hitoshi Okada and Naohide Oue and Wataru Yasui and Hans Clevers and Schoen, \{Robert E.\} and Jian Yu and Lin Zhang",

year = "2010",

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doi = "10.1073/pnas.1010430107",

language = "English",

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Qiu, W, Wang, X, Leibowitz, B, Liu, H, Barker, N, Okada, H, Oue, N, Yasui, W, Clevers, H, Schoen, RE, Yu, J & 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, vol. 107, no. 46, pp. 20027-20032. https://doi.org/10.1073/pnas.1010430107

Chemoprevention by nonsteroidal anti-inflammatory drugs eliminates oncogenic intestinal stem cells via SMAC-dependent apoptosis. / Qiu, Wei; Wang, Xinwei; Leibowitz, Brian et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 46, 16.11.2010, p. 20027-20032.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Chemoprevention by nonsteroidal anti-inflammatory drugs eliminates oncogenic intestinal stem cells via SMAC-dependent apoptosis

AU - Qiu, Wei

AU - Wang, Xinwei

AU - Leibowitz, Brian

AU - Liu, Hongtao

AU - Barker, Nick

AU - Okada, Hitoshi

AU - Oue, Naohide

AU - Yasui, Wataru

AU - Clevers, Hans

AU - Schoen, Robert E.

AU - Yu, Jian

AU - Zhang, Lin

PY - 2010/11/16

Y1 - 2010/11/16

N2 - 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.

AB - 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.

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M3 - Article

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SN - 0027-8424

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SP - 20027

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 46

ER -

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

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