Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL
Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL
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DOI：
10.1038/nm1627
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发表时间：
2007-09-01
期刊：
影响因子：
82.9
通讯作者：
Ashkenazi, Avi
中科院分区：
文献类型：
--
作者：
Wagner, Klaus W.;Punnoose, Elizabeth A.;Ashkenazi, Avi
DApo2L/TRAIL通过促凋亡受体DR4和DR5刺激癌细胞死亡，但该配体对肿瘤易感性的决定因素尚未完全确定。在胰腺癌、非小细胞肺癌和黑色素瘤细胞系中，GALNT14的表达与Apo2L/TRAIL的敏感性有关，在各种人类恶性肿瘤中，高达30%的标本显示GALNT14过表达。GALNT14的RNA干扰降低了细胞对Apo2L/TRAIL的敏感性，而过表达则增加了反应性。对DR5的生化分析确定了几个胞外结构域O-(N-乙酰氨基半乳糖-半乳糖-唾液酸)。序列比较预测了保守的胞外DR4和DR5O-糖基化位点；DR5位点的渐进性突变减弱了凋亡信号。O-糖基化促进了配体刺激的DR4和DR5的聚集，从而介导了启动凋亡的蛋白酶caspase-8的募集和激活。这些结果揭示了死亡受体O-糖基化和凋亡信号之间的新联系，为基于Apo2L/TRAIL的癌症治疗提供了潜在的预测生物标志物。
dApo2L/TRAIL stimulates cancer cell death through the proapoptotic receptors DR4 and DR5, but the determinants of tumor susceptibility to this ligand are not fully defined. mRNA expression of the peptidyl O-glycosyltransferase GALNT14 correlated with Apo2L/ TRAIL sensitivity in pancreatic carcinoma, non-small-cell lung carcinoma and melanoma cell lines, and up to 30% of samples from various human malignancies showed GALNT14 overexpression. RNA interference of GALNT14 reduced cellular Apo2L/ TRAIL sensitivity, whereas overexpression increased responsiveness. Biochemical analysis of DR5 identified several ectodomain O-(N-acetyl galactosamine-galactose-sialic acid) structures. Sequence comparison predicted conserved extracellular DR4 and DR5 O- glycosylation sites; progressive mutation of the DR5 sites attenuated apoptotic signaling. O- glycosylation promoted ligand-stimulated clustering of DR4 and DR5, which mediated recruitment and activation of the apoptosis-initiating protease caspase-8. These results uncover a new link between death-receptor O- glycosylation and apoptotic signaling, providing potential predictive biomarkers for Apo2L/TRAIL-based cancer therapy.