Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy
Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy
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DOI：
10.1074/jbc.m411781200
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发表时间：
2005-03-25
影响因子：
4.8
通讯作者：
Mollinedo, F
中科院分区：
文献类型：
--
作者：
Gajate, C;Mollinedo, F
在研究新型抗肿瘤药物Aplidin的作用机制时，我们发现了一种有效的新型细胞杀伤机制，该机制涉及在容纳死亡受体和凋亡相关分子的膜筏簇中形成Fas/CD 95驱动的支架。Fas，肿瘤坏死因子受体1，肿瘤坏死因子相关的凋亡诱导配体受体2/死亡受体5聚集成脂筏白血病Jurkat细胞Aplidin治疗后，Fas的存在是必不可少的凋亡。预先形成的膜结合Fas配体（FasL）以及下游信号分子，包括Fas相关的死亡结构域的蛋白，procaspase-8，procaspase-10，c-Jun氨基末端激酶，和Bid，也易位到脂筏，连接死亡受体外源性和线粒体内源性凋亡途径。阻断Fas/FasL相互作用可部分抑制Aplidin诱导的细胞凋亡。Aplidin迅速纳入膜筏，药物摄取被脂筏破坏抑制。肌动蛋白连接蛋白ezrin，膜突蛋白，RhoA，和RhoGDI被运送到Fas富集筏药物治疗的白血病细胞。破坏脂筏和干扰肌动蛋白细胞骨架阻止Fas聚集和凋亡。因此，Aplidin诱导的细胞凋亡涉及Fas激活的FasL独立的方式，并在Fas/FasL相互作用，自分泌的方式通过浓度的Fas，膜结合的FasL，和信号分子在膜筏。这些数据表明，肌动蛋白细胞骨架在形成Fas帽的主要作用，并强调了细胞凋亡信号分子富集筏的集群在细胞凋亡中的关键作用，作为死亡受体和下游信号分子的集中器，并作为一个强大的死亡信号发射的关键。
While investigating the mechanism of action of the novel antitumor drug Aplidin, we have discovered a potent and novel cell-killing mechanism that involves the formation of Fas/CD95-driven scaffolds in membrane raft clusters housing death receptors and apoptosis-related molecules. Fas, tumor necrosis factor-receptor 1, and tumor necrosis factor-related apoptosis-inducing ligand receptor 2/death receptor 5 were clustered into lipid rafts in leukemic Jurkat cells following Aplidin treatment, the presence of Fas being essential for apoptosis. Preformed membrane-bound Fas ligand (FasL) as well as downstream signaling molecules, including Fas-associated death domain-containing protein, procaspase-8, procaspase-10, c-Jun amino-terminal kinase, and Bid, were also translocated into lipid rafts, connecting death receptor extrinsic and mitochondrial intrinsic apoptotic pathways. Blocking Fas/FasL interaction partially inhibited Aplidin-induced apoptosis. Aplidin was rapidly incorporated into membrane rafts, and drug uptake was inhibited by lipid raft disruption. Actin-linking proteins ezrin, moesin, RhoA, and RhoGDI were conveyed into Fas-enriched rafts in drug-treated leukemic cells. Disruption of lipid rafts and interference with actin cytoskeleton prevented Fas clustering and apoptosis. Thus, Aplidin-induced apoptosis involves Fas activation in both a FasL-independent way and, following Fas/FasL interaction, an autocrine way through the concentration of Fas, membrane-bound FasL, and signaling molecules in membrane rafts. These data indicate a major role of actin cytoskeleton in the formation of Fas caps and highlight the crucial role of the clusters of apoptotic signaling molecule-enriched rafts in apoptosis, acting as concentrators of death receptors and downstream signaling molecules and as the linchpin from which a potent death signal is launched.