Intracellular Triggering of Fas Aggregation and Recruitment of Apoptotic Molecules into Fas-enriched Rafts in Selective Tumor Cell Apoptosis
| Autor: | A. Ulises Acuña, Consuelo Gajate, Antonio M. Santos-Beneit, Robert Jan Veldman, Faustino Mollinedo, Francisco Amat-Guerri, Esther del Canto-Jañez, Emilio Geijo |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
ET-18-OCH3
Programmed cell death Immunology Antineoplastic Agents Apoptosis HL-60 Cells Biology Article Fas ligand TNF-Related Apoptosis-Inducing Ligand chemistry.chemical_compound Membrane Microdomains Animals Humans Immunology and Allergy fas Receptor Lipid raft Death domain Membrane Glycoproteins Tumor Necrosis Factor-alpha Phospholipid Ethers U937 Cells Fas receptor Fas signaling Rats Cell biology Sphingomyelin Phosphodiesterase chemistry Protein Biosynthesis CD95 Hepatocytes death receptor antitumor ether lipid Apoptosis Regulatory Proteins Intracellular Edelfosine |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| DOI: | 10.1084/jem.20040213 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|