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.
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.
Benoit
Valérie
V
Laboratory of Medical Chemistry and Human Genetics, Center for Molecular and Cellular Therapy and Center for Research in Experimental Cancerology, University of Liege, Liege, Belgium.
Chariot
Alain
A
Delacroix
Laurence
L
Deregowski
Valérie
V
Jacobs
Nathalie
N
Merville
Marie-Paule
MP
Bours
Vincent
V
D000230:Adenocarcinoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000890:Anti-Infective Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D001665:Binding Sites; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000378:metabolism*; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013268:Stimulation, Chemical; D013450:Sulfones; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000890:Anti-Infective Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases; D003513:Cycloheximide; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009570:Nitriles; D018719:Erb-b2 Receptor Tyrosine Kinases; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; C416282:BAY 11-7085; C506386:CFLAR protein, human; C505530:CASP8 protein, human