Document Detail

Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy.
MedLine Citation:
PMID:  15659383     Owner:  NLM     Status:  MEDLINE    
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.
Consuelo Gajate; Faustino Mollinedo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-01-19
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  280     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2005 Mar 
Date Detail:
Created Date:  2005-03-21     Completed Date:  2005-04-21     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  11641-7     Citation Subset:  IM    
Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
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MeSH Terms
Actins / physiology
Antigens, CD95 / physiology
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Cytoskeleton / physiology*
Depsipeptides / pharmacology
Fas Ligand Protein
Jurkat Cells
Membrane Glycoproteins / metabolism*
Membrane Microdomains / metabolism*
Receptors, TNF-Related Apoptosis-Inducing Ligand
Receptors, Tumor Necrosis Factor / metabolism*
Receptors, Tumor Necrosis Factor, Type I / metabolism*
Reg. No./Substance:
0/Actins; 0/Antigens, CD95; 0/Antineoplastic Agents; 0/Depsipeptides; 0/FASLG protein, human; 0/Fas Ligand Protein; 0/Membrane Glycoproteins; 0/Receptors, TNF-Related Apoptosis-Inducing Ligand; 0/Receptors, Tumor Necrosis Factor; 0/Receptors, Tumor Necrosis Factor, Type I; 0/TNFRSF10B protein, human; 0/aplidine

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