Dumitru C A, Gulbins E
Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
Oncogene. 2006 Sep 14;25(41):5612-25. doi: 10.1038/sj.onc.1209568. Epub 2006 Apr 24.
We have previously shown that activation of the acid sphingomyelinase (ASM), the release of ceramide and the formation of ceramide-enriched membrane domains are central for the induction of apoptosis by CD95. Here, we demonstrate that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD95 activate the ASM via a redox mechanism resulting in release of ceramide and formation of ceramide-enriched membrane platforms. Ceramide-enriched membrane platforms serve to cluster DR5 upon stimulation. Antioxidants prevent TRAIL-mediated stimulation of ASM, the release of ceramide, the formation of ceramide-enriched membrane platforms and the induction of apoptosis by TRAIL. Further, ASM-deficient splenocytes fail to cluster DR5 in ceramide-enriched membrane domains upon TRAIL stimulation and resist TRAIL-induced apoptosis, events that were restored by addition of natural C(16)-ceramide. A dose-response analysis indicates that ceramide-enriched membrane platforms greatly sensitized tumor cells to TRAIL-induced apoptosis. Our data indicate that ceramide-enriched membrane platforms are required for the signaling of TRAIL-DR5 complexes under physiological conditions.
我们之前已经表明，酸性鞘磷脂酶（ASM）的激活、神经酰胺的释放以及富含神经酰胺的膜结构域的形成是CD95诱导细胞凋亡的核心环节。在此，我们证明肿瘤坏死因子相关凋亡诱导配体（TRAIL）和CD95通过氧化还原机制激活ASM，导致神经酰胺释放并形成富含神经酰胺的膜平台。富含神经酰胺的膜平台在受到刺激时可使DR5聚集。抗氧化剂可阻止TRAIL介导的ASM刺激、神经酰胺释放、富含神经酰胺的膜平台形成以及TRAIL诱导的细胞凋亡。此外，缺乏ASM的脾细胞在受到TRAIL刺激时无法在富含神经酰胺的膜结构域中使DR5聚集，并抵抗TRAIL诱导的细胞凋亡，而添加天然C(16)-神经酰胺可恢复这些事件。剂量反应分析表明，富含神经酰胺的膜平台可极大地使肿瘤细胞对TRAIL诱导的细胞凋亡敏感。我们的数据表明，在生理条件下，富含神经酰胺的膜平台是TRAIL-DR5复合物信号传导所必需的。
