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Rôles des caspases initiatrices et des sphingomyéline synthases dans l'apoptose induite par CD95L et TRAIL

By Elodie Lafont

Abstract

La mort cellulaire par apoptose est un mécanisme effecteur de la réponse immunitaire anti-tumorale. La liaison de ligands, dont TRAIL et CD95L, produits par des cellules immunitaires, sur des récepteurs de mort (DR pour Death Receptor), exprimés par les cellules tumorales, permet l'induction de l'apoptose. Ceci met en jeu différents événements dont la formation du DISC (Death Inducing Signalling Complex) et l'activation des caspases. De plus, le taux intracellulaire de céramide, un sphingolipide pro-apoptotique, augmente au cours de cette signalisation. L'objectif de cette thèse a été de clarifier le rôle des caspases initiatrices et du céramide dans l'apoptose induite par CD95L et TRAIL. Le rôle causal de la caspase 10, caspase initiatrice, dans l'induction de mort par CD95L est controversé. Nos travaux indiquent que cette protéase est impliquée dans la mort induite par CD95L en présence ou non de zVAD-fmk, un inhibiteur des caspases. Par ailleurs, nous montrons que la sphingomyéline synthase 1 (SMS1), qui synthétise de la sphingomyéline à partir de céramide, est inhibée de façon caspase-dépendante dans la signalisation de CD95. La SMS1 module l'induction de l'apoptose en réponse à CD95L et TRAIL. Ainsi, la surexpression de la SMS1 confère une protection vis-à-vis de la mort induite par ces ligands, tandis que la diminution de son expression sensibilise des cellules cancéreuses. Ce rôle protecteur dépendrait de la modulation de la formation du DISC et de la voie apoptotique mitochondriale. L'inhibition de cette enzyme pourrait donc permettre de sensibiliser des cellules cancéreuses à la mort induite par des agonistes des DR en modulant plusieurs étapes de l'apoptose.Apoptotic cell death is an effector mechanism involved in immune responses, and, particularly in anti-tumoral immune response. Binding of ligands, such as TRAIL and CD95L, which are produced by immune cells, on DR (Death Receptors) expressed by tumor cells, induces apoptosis. This involves, in particular, DISC (Death Inducing Signalling Complex) formation and caspases activation. Moreover, an increase of intracellular level of ceramide, a pro-apoptotic sphingolipid, has been observed during this signalling and might be involved in cell death induction. The aim of this PhD was to clarify initiator caspases and ceramide roles in CD95L and TRAIL induced apoptosis. Initiator caspase 10 involvement in CD95L-induced cell death is still controversed. Our results indicate that this protease is indeed involved in CD95L-induced cell death as well as in CD95L induced cell death in the presence of zVAD-fmk, a caspase inhibitor. Moreover, we show that sphingomyelin synthase 1 (SMS1), which is responsible for the synthesis of sphingomyelin from ceramide, is inhibited in CD95 signalling, in a caspase-dependent way, and more precisely in a caspase-8-dependent way. SMS1 could modulate CD95L- and TRAIL-induced cell death. Indeed, SMS1 overexpression is protective against CD95L- and TRAIL- induced cell death, whereas down-regulating SMS1 by RNA interference sensitizes cancer cells. Our results point out that SMS1 protective role might depend on DISC formation and apoptotic mitochondrial pathway modulations. Sphingomyelin synthesis inhibition might therefore be an original way to sensitize cancer cells towards DR agonists via putative apoptotic signalling modulations at several steps

Topics: Sciences du vivant
Year: 2011
OAI identifier: oai:thesesups.ups-tlse.fr:1353

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