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首页> 外文期刊>Apoptosis >Synthetic glycosidated phospholipids induce apoptosis through activation of FADD, caspase-8 and the mitochondrial death pathway
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Synthetic glycosidated phospholipids induce apoptosis through activation of FADD, caspase-8 and the mitochondrial death pathway

机译：合成的糖苷磷脂通过激活FADD，caspase-8和线粒体死亡途径来诱导细胞凋亡

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摘要

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.
机译：凋亡分别通过死亡受体介导的死亡诱导信号复合物（DISC）和线粒体来源的凋亡小体的形成，由外在和内在的信号传导途径调节。 Ino-C2-PAF是一种新型合成磷脂，具有令人印象深刻的抗增殖和凋亡诱导活性。关于它刺激细胞凋亡的信号传导途径知之甚少。在这里，我们显示该药物通过死亡受体途径的蛋白质诱导凋亡，从而导致内在凋亡途径的激活。 Ino-C2-PAF及其糖苷化衍生物Glc-PAF诱导的细胞凋亡取决于DISC组分FADD和caspase-8。这可以在FADD-/-和caspase-8-/-细胞中得到抑制，其中不会发生线粒体膜电位的破坏，细胞色素c的释放以及caspase-9，-8和-3的激活。此外，crmA，c-Flip或显性负性FADD的过度表达以及caspase-8抑制剂z-IETD-fmk的治疗均能保护Ino-C2-PAF诱导的细胞凋亡。细胞凋亡在没有CD95 / Fas-配体表达的情况下进行，并且与假定的死亡-配体/受体相互作用的阻断无关。此外，在CD95 / Fas-/-Jurkat细胞中不能抑制凋亡。线粒体或内质网（ER）中Bcl-2的表达强烈抑制Ino-C2-PAF-和Glc-PAF诱导的细胞凋亡。总之，Ino-C2-PAF和Glc-PAF触发CD95 / Fas不依赖配体和受体的非典型DISC，其依赖于通过ER和线粒体的内在凋亡途径。

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