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

Content Provider	Springer Nature Link
Author	Haefen, Clarissa Wendt, Jana Semini, Geo Sifringer, Marco Belka, Claus Radetzki, Silke Reutter, Werner Daniel, Peter T. Danker, Kerstin
Copyright Year	2011
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.
Starting Page	636
Ending Page	651
Page Count	16
File Format	PDF
ISSN	13608185
Journal	Apoptosis
Volume Number	16
Issue Number	6
e-ISSN	1573675X
Language	English
Publisher	Springer US
Publisher Date	2011-03-25
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Synthetic phospholipid analogs DISC Apoptosis Mitochondrial pathway Oncology Cell Biology Cancer Research Virology Biochemistry
Content Type	Text
Resource Type	Article
Subject	Pharmaceutical Science Biochemistry (medical) Cell Biology Clinical Biochemistry Cancer Research Pharmacology

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