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

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 α (TNF-α) stimulation leads to an early caspase-8-dependent HER-2 cleavage in MCF7 A/Z breast adenocarcinoma cells defective for nuclear factor κB (NFκB) activation. We show that the antiapoptotic transcription factor NFκB 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-α-induced apoptosis pathway because ectopic expression of an uncleavable HER-2 protects NFκB-defective cells against TNF-α-mediated cell death. Therefore, we propose an original model in which NFκB exerts a new antiapoptotic function by counteracting TNF-α-triggered cleavage of the HER-2 survival factor.