Liu Z, Li H, Wu X, Yoo B H, Yan S R, Stadnyk A W, Sasazuki T, Shirasawa S, LaCasse E C, Korneluk R G, Rosen K V
Department of Pediatrics, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia, Canada.
Oncogene. 2006 Dec 14;25(59):7680-90. doi: 10.1038/sj.onc.1209753. Epub 2006 Jun 26.
Detachment of normal epithelial cells from the extracellular matrix triggers apoptosis, a phenomenon called anoikis. Conversely, carcinoma cells tend to be relatively more anoikis-resistant than their normal counterparts, and this increased resistance represents a critical feature of the malignant phenotype. Mechanisms that control susceptibility and resistance to anoikis are not fully understood. It is now known that detachment of non-malignant epithelial cells triggers both pro- and antiapoptotic signals, and it is the balance between these signals and the duration of detachment that determine further fate of the cells. Detachment-induced antiapoptotic events delay anoikis and if cells reattach relatively soon after detachment they survive. Direct regulators of apoptosis responsible for this delay of anoikis are unknown. We found that detachment of non-malignant intestinal epithelial cells triggers upregulation of inhibitors of apoptosis protein (IAP) family, such as X-chromosome-linked inhibitor of apoptosis protein and cellular inhibitor of apoptosis-2 (cIAP2). We demonstrated that this upregulation requires detachment-dependent activation of the transcription factor nuclear factor-kappaB. We further observed that various IAP antagonists accelerate anoikis, indicating that upregulation of the IAPs delays detachment-triggered apoptosis. We conclude that the IAPs are important regulators of the balance between detachment-triggered life and death signals. Perhaps, not by coincidence, these proteins are often upregulated in carcinomas, tumors composed of cells that tend to be anoikis-resistant.
正常上皮细胞与细胞外基质脱离会引发凋亡，这种现象称为失巢凋亡。相反，癌细胞往往比其正常对应细胞对失巢凋亡具有相对更强的抗性，而这种增加的抗性是恶性表型的一个关键特征。控制对失巢凋亡易感性和抗性的机制尚未完全了解。现在已知非恶性上皮细胞的脱离会触发促凋亡和抗凋亡信号，而这些信号之间的平衡以及脱离的持续时间决定了细胞的进一步命运。脱离诱导的抗凋亡事件会延迟失巢凋亡，如果细胞在脱离后相对较快地重新附着，它们就能存活。导致失巢凋亡延迟的凋亡直接调节因子尚不清楚。我们发现非恶性肠上皮细胞的脱离会触发凋亡抑制蛋白（IAP）家族的上调，如X染色体连锁凋亡抑制蛋白和细胞凋亡抑制因子2（cIAP2）。我们证明这种上调需要转录因子核因子-κB的脱离依赖性激活。我们进一步观察到各种IAP拮抗剂会加速失巢凋亡，表明IAP的上调会延迟脱离触发的凋亡。我们得出结论，IAPs是脱离触发的生死信号之间平衡的重要调节因子。也许并非巧合的是，这些蛋白在癌（由倾向于对失巢凋亡具有抗性的细胞组成的肿瘤）中经常上调。
