FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells

Oncogene. 2004 Oct 14;23(47):7753-60. doi: 10.1038/sj.onc.1208051.


Tumors have developed several forms of resistance to receptor-induced cell death. Here, we show that malignant mesothelial (MM) cell lines as well as primary MM cells and normal mesothelial (NM) cells express Fas and TNF-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5. We found that, although Fas expression levels are comparable, only MM cells are resistant to cell death. Furthermore, MM cells show resistance to TRAIL-induced apoptosis. Caspase-8 (FLICE) is not activated by death receptors triggering in malignant cells whereas it is well activated by nonreceptor stimuli, such as UV radiation. We found that FLIP (FLICE-Inhibitory Protein) is constitutively expressed in all MM cell lines and is more expressed in primary MM cells than in NM cells. Knockdown of FLIP expression in MM cell lines, by a FLIPsiRNA, re-established the normal response to apoptosis induced by Fas or DR4/DR5, which was blocked by pretreatment with the caspase-8 inhibitor z-IETD-fmk. These results indicate that MM cells develop an intrinsic resistance to apoptosis induced by death receptors upregulating the expression of the antiapoptotic protein c-FLIP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Base Sequence
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Caspase 8
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Cysteine Proteinase Inhibitors / pharmacology
  • DNA Primers
  • Epithelium / physiology
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Mesothelioma / genetics
  • Mesothelioma / pathology*
  • Oligopeptides / pharmacology
  • Ploidies
  • RNA, Small Interfering / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transfection
  • fas Receptor / physiology


  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • DNA Primers
  • Intracellular Signaling Peptides and Proteins
  • Oligopeptides
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNFRSF10A protein, human
  • TNFRSF10B protein, human
  • benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone
  • fas Receptor
  • CASP8 protein, human
  • Caspase 8
  • Caspases