English
español
Please use this identifier to cite or link to this item:
http://hdl.handle.net/10261/11705
Share/Impact:
Statistics |
![]() ![]() ![]() |
|
|
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE | |||
|
Title: | Intracellular Triggering of Fas Aggregation and Recruitment of Apoptotic Molecules into Fas-enriched Rafts in Selective Tumor Cell Apoptosis |
Authors: | Gajate, Consuelo ; Canto-Jañez, Esther del; Acuña, A. Ulises ![]() ![]() |
Keywords: | CD95 Fas signaling Death receptor Antitumor ether lipid ET-18-OCH3 |
Issue Date: | 2-Aug-2004 |
Publisher: | Rockefeller University Press |
Citation: | Journal of Experimental Medicine 200(3): 353-365 (2004) |
Abstract: | 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. |
Publisher version (URL): | http://www.jem.org/cgi/doi/10.1084/jem.20040213 |
URI: | http://hdl.handle.net/10261/11705 |
DOI: | http://dx.doi.org/10.1084/jem.20040213 |
ISSN: | 0022-1007 |
Appears in Collections: | (IN) Artículos (IQOG) Artículos (IQFR) Artículos (IBMCC) Artículos |
Show full item record
Review this work
Review this work
WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.