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

Kenneth H. Shain, Terry H. Landowski, William S. Dalton

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

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 β1 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-FLIPL) cytosolic solubility compared with nonadhered cells. Cytosolic c-FLIPL 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-FLIPL in the death-inducing signal complex prevented procaspase-8 processing and activation of the effector phase of apoptosis. Adhesion to fibronectin increased c-FLIPL cytosolic solubility and availability for FADD binding by redistributing c-FLIPL from a preexisting membrane-associated fraction. Increased cytosolic availability of c-FLIPL 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-FLIPL.

Original languageEnglish (US)
Pages (from-to)2544-2553
Number of pages10
JournalJournal of Immunology
Volume168
Issue number5
DOIs
StatePublished - Mar 1 2002

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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