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[Cancer Research 64, 2684-2691, April 15, 2004]
© 2004 American Association for Cancer Research

Regular Articles

Caspase-8-Dependent HER-2 Cleavage in Response to Tumor Necrosis Factor {alpha} Stimulation Is Counteracted by Nuclear Factor {kappa}B through c-FLIP-L Expression

Valérie Benoit1, Alain Chariot1, Laurence Delacroix2, Valérie Deregowski1, Nathalie Jacobs2, Marie-Paule Merville1 and Vincent Bours1

1 Laboratory of Medical Chemistry and Human Genetics, Center for Molecular and Cellular Therapy and 2 Center for Research in Experimental Cancerology, University of Liege, Liege, Belgium

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 {kappa}B (NF{kappa}B) activation. We show that the antiapoptotic transcription factor NF{kappa}B 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 NF{kappa}B-defective cells against TNF-{alpha}-mediated cell death. Therefore, we propose an original model in which NF{kappa}B exerts a new antiapoptotic function by counteracting TNF-{alpha}-triggered cleavage of the HER-2 survival factor.




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Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
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Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2004 by the American Association for Cancer Research.