Intracellular triggering of Fas aggregation and recruitment of apoptotic molecules into Fas-enriched rafts in selective tumor cell apoptosis.
Intracellular triggering of Fas aggregation and recruitment of apoptotic molecules into Fas-enriched rafts in selective tumor cell apoptosis.
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DOI：
10.1084/jem.20040213
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发表时间：
2004-08-02
期刊：
影响因子：
--
通讯作者：
Mollinedo F
中科院分区：
文献类型：
--
作者：
Gajate C;Del Canto-Jañez E;Acuña AU;Amat-Guerri F;Geijo E;Santos-Beneit AM;Veldman RJ;Mollinedo F
我们发现了一种新的特异性的细胞杀伤机制，其介导的选择性摄取的抗肿瘤药物1-O-十八烷基-2-O-甲基-rac-甘油-3-磷酸胆碱（ET-18-OCH 3，Edelfosine）进入肿瘤细胞的脂筏，随后与Fas死亡受体（也称为APO-1或CD 95）共聚集和招募凋亡分子进入Fas富集筏。药物敏感性依赖于药物摄取和Fas表达，而不管靶细胞中是否存在其他主要死亡受体，如肿瘤坏死因子（TNF）受体1或TNF相关凋亡诱导配体R2/DR 5。在Fas缺陷和Fas转染的细胞中的药物显微注射实验不能掺入外源性ET-18-OCH 3，表明Fas是细胞内激活的。Fas胞内结构域的部分缺失阻止了细胞凋亡。与正常淋巴细胞不同，白血病T细胞将ET-18-OCH 3掺入与Fas共聚集的筏中并进行凋亡。Fas相关的死亡结构域蛋白，procaspase-8，procaspase-10，c-Jun氨基末端激酶和Bid被招募到筏中，连接Fas和线粒体信号通路。筏的聚集是必要的，但不足以ET-18-OCH 3介导的细胞死亡，Fas被要求作为凋亡触发。ET-18-OCH 3介导的细胞凋亡不需要鞘磷脂酶激活。正常细胞，包括人和大鼠肝细胞，不掺入ET-18-OCH 3，并保留。这种机制代表了Fas在肿瘤细胞中的第一次选择性激活。我们的数据为开发更有针对性的治疗方法提供了一个框架，这些治疗方法可导致细胞内Fas激活和下游信号分子募集到富含Fas的筏中。
We have discovered a new and specific cell-killing mechanism mediated by the selective uptake of the antitumor drug 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3, Edelfosine) into lipid rafts of tumor cells, followed by its coaggregation with Fas death receptor (also known as APO-1 or CD95) and recruitment of apoptotic molecules into Fas-enriched rafts. Drug sensitivity was dependent on drug uptake and Fas expression, regardless of the presence of other major death receptors, such as tumor necrosis factor (TNF) receptor 1 or TNF-related apoptosis-inducing ligand R2/DR5 in the target cell. Drug microinjection experiments in Fas-deficient and Fas-transfected cells unable to incorporate exogenous ET-18-OCH3 demonstrated that Fas was intracellularly activated. Partial deletion of the Fas intracellular domain prevented apoptosis. Unlike normal lymphocytes, leukemic T cells incorporated ET-18-OCH3 into rafts coaggregating with Fas and underwent apoptosis. Fas-associated death domain protein, procaspase-8, procaspase-10, c-Jun amino-terminal kinase, and Bid were recruited into rafts, linking Fas and mitochondrial signaling routes. Clustering of rafts was necessary but not sufficient for ET-18-OCH3–mediated cell death, with Fas being required as the apoptosis trigger. ET-18-OCH3–mediated apoptosis did not require sphingomyelinase activation. Normal cells, including human and rat hepatocytes, did not incorporate ET-18-OCH3 and were spared. This mechanism represents the first selective activation of Fas in tumor cells. Our data set a framework for the development of more targeted therapies leading to intracellular Fas activation and recruitment of downstream signaling molecules into Fas-enriched rafts.
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影响因子：
32.4
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