Caspase-8-dependent HER-2 cleavage in response to tumor necrosis factor alpha stimulation is counteracted by nuclear factor kappaB through c-FLIP-L expression

Cancer Res. 2004 Apr 15;64(8):2684-91. doi: 10.1158/0008-5472.can-03-2914.

Abstract

The oncoprotein HER-2/neu is a prosurvival factor, and its overexpression has been correlated with poor prognosis in patients with breast cancer. We report that HER-2 is a new substrate for caspase-8 and that tumor necrosis factor alpha (TNF-alpha) stimulation leads to an early caspase-8-dependent HER-2 cleavage in MCF7 A/Z breast adenocarcinoma cells defective for nuclear factor kappaB (NFkappaB) activation. We show that the antiapoptotic transcription factor NFkappaB counteracts this cleavage through induction of the caspase-8 inhibitor c-FLIP. Our results also demonstrate that this HER-2 cleavage contributes to the TNF-alpha-induced apoptosis pathway because ectopic expression of an uncleavable HER-2 protects NFkappaB-defective cells against TNF-alpha-mediated cell death. Therefore, we propose an original model in which NFkappaB exerts a new antiapoptotic function by counteracting TNF-alpha-triggered cleavage of the HER-2 survival factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / enzymology
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Anti-Infective Agents / pharmacology
  • Apoptosis / physiology
  • Binding Sites
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / metabolism*
  • Caspase 8
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Cell Line, Tumor
  • Cycloheximide / pharmacology
  • Enzyme Activation
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Nitriles
  • Receptor, ErbB-2 / biosynthesis
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Stimulation, Chemical
  • Sulfones
  • Transcriptional Activation
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Anti-Infective Agents
  • BAY 11-7085
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Carrier Proteins
  • Caspase Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Nitriles
  • Sulfones
  • Tumor Necrosis Factor-alpha
  • Cycloheximide
  • Receptor, ErbB-2
  • CASP8 protein, human
  • Caspase 8
  • Caspases