High level of cFLIP correlates with resistance to death receptor-induced apoptosis in bladder carcinoma cells

Anticancer Res. Mar-Apr 2003;23(2B):1213-8.

Abstract

Background: The cellular form of FLICE-inhibitory protein (cFLIP) blocks death receptor-induced apoptosis and has been implicated in tumour progression. cFLIP interacts with caspase-8, thereby preventing activation of the caspase cascade. In this study we investigated the endogenous expression of cFLIP and caspase-8 in bladder carcinoma cells in relation to their sensitivity to death receptor-ligation.

Materials and methods: Apoptosis was induced by agonistic anti-CD95 mAbs or recombinant TRAIL and quantified by the TUNEL technique. The relative mRNA expression of cFLIP and caspase-8 was quantified by real-time PCR. Stable expression of cFLIP long (cFLIPL) was obtained by retroviral transduction.

Results: The relative ratio of cFLIP and caspase-8 was directly correlated to resistance to anti-CD95 or TRAIL-mediated apoptosis. Overexpression of cFLIPL shifted the responsiveness towards resistant status.

Conclusion: cFLIP is an important determinant of susceptibility to death receptor-induced apoptosis in bladder carcinomas and could function as a prognostic marker for death receptor sensitivity in future immune therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carcinoma / metabolism
  • Carcinoma / pathology*
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Caspase 8
  • Caspase 9
  • Caspases / biosynthesis
  • Caspases / genetics
  • Caspases / physiology
  • Drug Resistance, Neoplasm
  • Enzyme Induction
  • Gene Expression Regulation, Neoplastic
  • Humans
  • In Situ Nick-End Labeling
  • Intracellular Signaling Peptides and Proteins*
  • Jurkat Cells / metabolism
  • Jurkat Cells / pathology
  • Membrane Glycoproteins / pharmacology
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / drug effects
  • Receptors, Tumor Necrosis Factor / physiology*
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / pharmacology
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology*
  • fas Receptor / drug effects
  • fas Receptor / physiology*

Substances

  • Antibodies, Monoclonal
  • Apoptosis Regulatory Proteins
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • RNA, Messenger
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9
  • Caspases