Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells
Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells
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DOI：
10.1038/sj.onc.1209753
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发表时间：
2006-12-01
期刊：
影响因子：
8
通讯作者：
Rosen, K. V.
中科院分区：
文献类型：
--
作者：
Liu, Z.;Li, H.;Rosen, K. V.
正常上皮细胞与细胞外基质的分离触发细胞凋亡，这种现象称为失巢凋亡。相反，癌细胞倾向于比它们的正常对应物相对更抗失巢凋亡，并且这种增加的抗性代表恶性表型的关键特征。控制失巢凋亡的易感性和抵抗性的机制还不完全清楚。现在已知，非恶性上皮细胞的脱离触发促凋亡信号和抗凋亡信号，并且这些信号和脱离持续时间之间的平衡决定了细胞的进一步命运。脱落诱导的抗凋亡作用可以延缓失巢凋亡，如果脱落后细胞相对较早地重新附着，它们就能存活.负责这种失巢凋亡延迟的细胞凋亡的直接调节因子是未知的。我们发现，非恶性肠上皮细胞的脱离触发凋亡蛋白（IAP）家族的抑制剂的上调，例如X染色体连锁的凋亡蛋白抑制剂和细胞凋亡抑制剂-2（cIAP 2）。我们证明，这种上调需要转录因子核因子-κ B的转录依赖性激活。我们进一步观察到各种IAP拮抗剂加速失巢凋亡，表明IAP的上调延迟了脱离触发的凋亡。我们的结论是，IAP是重要的调节器之间的脱离触发的生命和死亡信号的平衡。也许，并非巧合，这些蛋白质在癌中经常上调，这些肿瘤由倾向于抗失巢凋亡的细胞组成。
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 susceptibilityand 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 relativelysoo n 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-kappa B. 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.