University of Pittsburgh Cancer Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):20027-32. doi: 10.1073/pnas.1010430107. Epub 2010 Nov 1.
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.
非甾体抗炎药（NSAIDs）如舒林酸能有效预防人类和啮齿动物模型的结肠癌。然而，它们的细胞靶点和潜在机制仍难以捉摸。我们发现，饮食中的舒林酸诱导细胞凋亡，从而去除 APC（Min/+）小鼠中具有核或磷酸化 β-catenin 的肠干细胞。NSAIDs 还能诱导人结肠息肉中的细胞凋亡，并有效地去除具有异常 Wnt 信号的细胞。此外，线粒体促凋亡蛋白 SMAC 的缺失通过阻止细胞凋亡和去除具有核或磷酸化 β-catenin 的干细胞，减弱了舒林酸在 APC（Min/+）小鼠中的肿瘤抑制作用。这些结果表明，NSAIDs 通过诱导细胞凋亡有效预防结肠癌，其机制在于消除因致癌事件而异常激活的干细胞。
