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Caspase-8-dependent HER-2 cleavage in response to tumor necrosis factor alpha stimulation is counteracted by nuclear

Valérie Benoit1, Alain Chariot, Laurence Delacroix

  • 1Laboratory of Medical Chemistry and Human Genetics, Center for Molecular and Cellular Therapy and Center for Research in Experimental Cancerology, University of Liege, Liege, Belgium.

Cancer Research
|April 17, 2004
PubMed

Insights

The oncoprotein HER-2/neu, a factor promoting cell survival, is cleaved by caspase-8 upon tumor necrosis factor alpha (TNF-alpha) stimulation. Nuclear factor kappaB (NFkappaB) activation inhibits this cleavage, revealing a new anti-apoptotic role for NFkappaB in breast cancer cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Signaling

Background:

  • HER-2/neu oncoprotein overexpression is linked to poor prognosis in breast cancer.
  • HER-2/neu acts as a prosurvival factor, influencing cancer cell survival and proliferation.
  • Tumor necrosis factor alpha (TNF-alpha) is a key cytokine involved in inflammation and apoptosis.

Purpose of the Study:

  • To investigate the role of HER-2/neu in TNF-alpha-induced apoptosis.
  • To identify new substrates and regulatory mechanisms of caspase-8 in breast cancer cells.
  • To elucidate the interplay between HER-2/neu cleavage, NFkappaB signaling, and apoptosis.

Main Methods:

  • Utilized MCF7 A/Z breast adenocarcinoma cells with defective NFkappaB activation.
  • Stimulated cells with TNF-alpha to induce caspase-8 activity and HER-2 cleavage.
  • Assessed HER-2 cleavage using Western blotting and analyzed the role of NFkappaB and c-FLIP.

Main Results:

  • Demonstrated that HER-2/neu is a novel substrate for caspase-8.
  • Showed that TNF-alpha stimulation triggers caspase-8-dependent HER-2 cleavage in NFkappaB-defective cells.
  • Confirmed that NFkappaB activation counteracts HER-2 cleavage by inducing the caspase-8 inhibitor c-FLIP.
  • Established that HER-2 cleavage contributes to TNF-alpha-induced apoptosis, as preventing cleavage protects cells.

Conclusions:

  • Proposed a novel model where NFkappaB exerts an antiapoptotic function by inhibiting TNF-alpha-triggered HER-2 cleavage.
  • Highlighted a new mechanism by which NFkappaB signaling modulates cell survival pathways in breast cancer.
  • Identified HER-2 cleavage as a critical step in TNF-alpha-mediated apoptosis, offering potential therapeutic targets.

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