Lipid raft‐mediated Fas/CD95 apoptotic signaling in leukemic cells and normal leukocytes and therapeutic implications

[摘要] Plasmamembraneisnowrecognizedtocontaintightlypackedcholesterol/sphingolipid‐richdomains,knownaslipidormembranerafts,whicharemoreorderedthanthesurroundinglipidbilayer.Lipidraftsarecrucialforthecompartmentalizationofsignalingprocessesinthemembrane,mostlyinvolvedincellsurvivalandimmuneresponse.However,inthelast15years,alargebodyofevidencehasalsoidentifiedraftplatformsasscaffoldsfortherecruitmentandclusteringofdeathreceptorFas/CD95anddownstreamsignalingmolecules,leadingtotheconceptofdeath‐promotinglipidrafts.Thisraft‐Fas/CD95coclusteringwasfirstdescribedattheearly2000sastheunderlyingmechanismfortheproapoptoticactionofthealkylphospholipidanalogedelfosineinleukemiccells,hencefacilitatingprotein–proteininteractionsandconveyingapoptoticsignalsindependentlyofFas/CD95ligand.EdelfosineinducesapoptosisinhematologiccancercellsandactivatedT‐lymphocytes.Fas/CD95raftcoclusteringisalsopromotedbyFas/CD95ligand,agonisticFas/CD95antibodies,andadditionalantitumordrugs.Thus,deathreceptorrecruitmentinraftsisaphysiologicprocessleadingtocelldemisethatcanbepharmacologicallymodulated.Thisredistributionandlocalaccumulationofapoptoticmoleculesinmembranerafts,whichareusuallyaccompaniedbydisplacementofsurvivalsignalingmolecules,highlighthowalterationsintheapoptosis/survivalsignalingbalanceinspecializedmembraneregionsmodulatecellfate.Membraneraftsmightalsomodulateapoptoticandnonapoptoticdeathreceptorsignaling.Here,wediscusstheroleoflipidraftsinFas/CD95‐mediatedapoptoticcellsignalinginhematologiccancercellsandnormalleukocytes,withaspecialemphasisontheirinvolvementasputativetherapeutictargetsincancerandautoimmunediseases...

[学科分类] 生理学

[关键词] death receptor;cancer;autoimmune disease