Keywords :
Adenocarcinoma/enzymology/metabolism/pathology; Anti-Infective Agents/pharmacology; Apoptosis/physiology; Binding Sites; Breast Neoplasms/enzymology/metabolism/pathology; CASP8 and FADD-Like Apoptosis Regulating Protein; Carrier Proteins/metabolism; Caspase 8; Caspases/antagonists & inhibitors/metabolism; Cell Line, Tumor; Cycloheximide/pharmacology; HER-2; Intracellular Signaling Peptides and Proteins; MCF7; NF kappa B; Sulfones; Transcriptional Activation; Tumor Necrosis Factor-alpha/pharmacology
Abstract :
[en] 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.
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