Kohli Manu, Yu Jian, Seaman Craig, Bardelli Alberto, Kinzler Kenneth W, Vogelstein Bert, Lengauer Christoph, Zhang Lin
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.
Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16897-902. doi: 10.1073/pnas.0403405101. Epub 2004 Nov 19.
Nonsteroidal antiinflammatory drugs (NSAIDs) form a paradigm for the chemoprevention of cancer, preventing colonic tumor progression in both experimental animals and humans. However, the mechanisms underlying the antineoplastic effects of NSAIDs are currently unclear. We found that the mitochondrial second mitochondrial-derived activator of caspase (SMAC)/direct inhibitor of apoptosis protein-binding protein with low pI (Diablo) protein translocates into the cytosol during NSAID-induced apoptosis in colon cancer cells. When SMAC/Diablo is disrupted by homologous recombination and RNA interference in these cells, the NSAID-induced apoptosis is abrogated. Biochemical markers of apoptosis, such as caspase activation, cytosolic release of cytochrome c and apoptosis-inducing factor, and mitochondrial membrane potential change, are accordingly decreased. These results establish that SMAC/Diablo is essential for the apoptosis induced by NSAIDs in colon cancer cells.
非甾体抗炎药（NSAIDs）构成了癌症化学预防的范例，在实验动物和人类中均可预防结肠肿瘤进展。然而，NSAIDs抗肿瘤作用的潜在机制目前尚不清楚。我们发现，在NSAIDs诱导结肠癌细胞凋亡过程中，线粒体半胱天冬酶激活剂（SMAC）/低pI值凋亡蛋白直接抑制因子结合蛋白（Diablo）会转位至胞质溶胶。当通过同源重组和RNA干扰破坏这些细胞中的SMAC/Diablo时，NSAIDs诱导的凋亡被消除。相应地，凋亡的生化标志物，如半胱天冬酶激活、细胞色素c和凋亡诱导因子的胞质释放以及线粒体膜电位变化均会降低。这些结果表明，SMAC/Diablo对于NSAIDs诱导结肠癌细胞凋亡至关重要。
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