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

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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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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  • DOI: https://doi.org/10.1038/sj.onc.1209568

Keywords

  • ceramide
  • acid sphingomyelinase
  • TRAIL
  • apoptosis
  • tumor therapy
  • redox

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