Chemoprevention by nonsteroidal anti-inflammatory drugs eliminates oncogenic intestinal stem cells via SMAC-dependent apoptosis.
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 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 β-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.
University of Pittsburgh Cancer Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Wei
W
Qiu
Xinwei
X
Wang
Brian
B
Leibowitz
Hongtao
H
Liu
Nick
N
Barker
Hitoshi
H
Okada
Naohide
N
Oue
Wataru
W
Yasui
Hans
H
Clevers
Robert E
RE
Schoen
Jian
J
Yu
Lin
L
Zhang
D011125:Adenomatous Polyposis Coli / Q000378:metabolism; D000368:Aged; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D018890:Chemoprevention; D003111:Colonic Polyps / Q000188:drug therapy / Q000473:pathology; D005260:Female; D006801:Humans; D007422:Intestines / Q000187:drug effects / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013467:Sulindac / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C412403:DIABLO protein, human; C499605:Diablo protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D013467:Sulindac