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TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

Oncogene volume 25, pages 5612–5625 (2006)Cite this article

Abstract

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 C16-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.

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Acknowledgements

The studies were supported by the Association of International Cancer Research, Deutsche Krebshilfe grant 10-2238-Gu2, DFG-grant Gu 335/13-1 and the Graduiertenkolleg 1045/1 to EG.

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  1. Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany

    C A Dumitru & E Gulbins

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Correspondence to E Gulbins.

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Dumitru, C., Gulbins, E. TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis. Oncogene 25, 5612–5625 (2006). https://doi.org/10.1038/sj.onc.1209568

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