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Synthetic glycosidated phospholipids induce apoptosis through activation of FADD, caspase-8 and the mitochondrial death pathway

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Abstract

Apoptosis is modulated by extrinsic and intrinsic signaling pathways through the formation of the death receptor-mediated death-inducing signaling complex (DISC) and the mitochondrial-derived apoptosome, respectively. Ino-C2-PAF, a novel synthetic phospholipid shows impressive antiproliferative and apoptosis-inducing activity. Little is known about the signaling pathway through which it stimulates apoptosis. Here, we show that this drug induces apoptosis through proteins of the death receptor pathway, which leads to an activation of the intrinsic apoptotic pathway. Apoptosis induced by Ino-C2-PAF and its glucosidated derivate, Glc-PAF, was dependent on the DISC components FADD and caspase-8. This can be inhibited in FADD−/− and caspase-8−/− cells, in which the breakdown of the mitochondrial membrane potential, release of cytochrome c and activation of caspase-9, -8 and -3 do not occur. In addition, the overexpression of crmA, c-Flip or dominant negative FADD as well as treatment with the caspase-8 inhibitor z-IETD-fmk protected against Ino-C2-PAF-induced apoptosis. Apoptosis proceeds in the absence of CD95/Fas-ligand expression and is independent of blockade of a putative death-ligand/receptor interaction. Furthermore, apoptosis cannot be inhibited in CD95/Fas−/− Jurkat cells. Expression of Bcl-2 in either the mitochondria or the endoplasmic reticulum (ER) strongly inhibited Ino-C2-PAF- and Glc-PAF-induced apoptosis. In conclusion, Ino-C2-PAF and Glc-PAF trigger a CD95/Fas ligand- and receptor-independent atypical DISC that relies on the intrinsic apoptotic pathway via the ER and the mitochondria.

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Authors and Affiliations

  1. Department of Anaesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353, Berlin, Germany

    Clarissa von Haefen & Marco Sifringer

  2. Department of Haematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Buch, Berlin, Germany

    Jana Wendt, Silke Radetzki & Peter T. Daniel

  3. Department of Radiation Oncology, University of Munich, Munich, Germany

    Claus Belka

  4. Institute of Biochemistry, Campus Virchow Klinikum, University Medical Center Charité, Berlin, Germany

    Geo Semini & Kerstin Danker

  5. Institute of Biochemistry and Molecular Biology, Campus Benjamin Franklin, Berlin, Germany

    Werner Reutter

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  1. Clarissa von Haefen
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  2. Jana Wendt
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  3. Geo Semini
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  4. Marco Sifringer
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  5. Claus Belka
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  6. Silke Radetzki
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  7. Werner Reutter
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  8. Peter T. Daniel
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  9. Kerstin Danker
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Correspondence to Clarissa von Haefen.

Additional information

Peter T. Daniel and Kerstin Danker—shared senior authorship.

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von Haefen, C., Wendt, J., Semini, G. et al. Synthetic glycosidated phospholipids induce apoptosis through activation of FADD, caspase-8 and the mitochondrial death pathway. Apoptosis 16, 636–651 (2011). https://doi.org/10.1007/s10495-011-0592-2

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  • DOI: https://doi.org/10.1007/s10495-011-0592-2

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