Intracellular triggering of fas aggregation and recruitment of apoptotic molecules into fas-enriched rafts in selective tumor cell apoptosis

被引:176
作者
Gajate, C
del Canto-Jañez, E
Acuña, AU
Amat-Guerri, F
Geijo, E
Santos-Beneit, AM
Veldman, RJ
Mollinedo, F
机构
[1] Univ Salamanca, CSIC, Inst Biol Mol & Celular Canc, Ctr Invest Canc, E-37007 Salamanca, Spain
[2] CSIC, Inst Quim Fis Rocasolano, E-28006 Madrid, Spain
[3] CSIC, Inst Quim Organ, E-28006 Madrid, Spain
[4] Univ Miguel Hernandez, CSIC, Inst Neurociencias, E-03550 Alicante, Spain
关键词
CD95; Fas signaling; death receptor; antitumor ether lipid; ET-18-OCH3;
D O I
10.1084/jem.20040213
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 under-went 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.
引用
收藏
页码:353 / 365
页数:13
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