Adhesion-mediated intracellular redistribution of c-Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein-long confers resistance to CD95-induced apoptosis in hematopoietic cancer cell lines.
Evasion of immune surveillance is a key step in malignant progression. Interactions between transformed hematopoietic cells and their environment may initiate events that confer resistance to apoptosis and facilitate immune evasion. In this report, we demonstrate that beta(1) integrin-mediated adhesion to fibronectin inhibits CD95-induced caspase-8 activation and apoptosis in hematologic tumor cell lines. This adhesion-dependent inhibition of CD95-mediated apoptosis correlated with enhanced c-Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein-long (c-FLIP(L)) cytosolic solubility compared with nonadhered cells. Cytosolic c-FLIP(L) protein preferentially associated with cytosolic Fas-associated death domain protein (FADD) and localized to the death-inducing signal complex after CD95 ligation in adherent cells. The incorporation of c-FLIP(L) in the death-inducing signal complex prevented procaspase-8 processing and activation of the effector phase of apoptosis. Adhesion to fibronectin increased c-FLIP(L) cytosolic solubility and availability for FADD binding by redistributing c-FLIP(L) from a preexisting membrane-associated fraction. Increased cytosolic availability of c-FLIP(L) for FADD binding was not related to increased levels of RNA or protein synthesis. These data show that adhesion of anchorage-independent cells to fibronectin provides a novel mechanism of resistance to CD95-mediated programmed cell death by regulating the cellular localization and availability of c-FLIP(L).
Shain
Kenneth H
KH
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA.
Landowski
Terry H
TH
Dalton
William S
WS
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000378:metabolism*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion; D003600:Cytosol / Q000378:metabolism; D004792:Enzyme Precursors / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D005353:Fibronectins / Q000494:pharmacology; D019337:Hematologic Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D008954:Models, Biological; D021381:Protein Transport; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D004792:Enzyme Precursors; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D005353:Fibronectins; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases