Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity.Reportar como inadecuado

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* Corresponding author 1 CIRID - Composantes innées de la réponse immunitaire et différenciation 2 Animalerie spécialisée 3 CRRET - Laboratoire de recherche sur la croissance cellulaire, la réparation et la régénération tissulaires 4 CRCNA - Centre de Recherche en Cancérologie - Nantes - Angers 5 Centre génomique fonctionnelle 6 Récepteur de mort et échappement tumoral Irset - Institut de recherche, santé, environnement et travail Rennes

Abstract : Binding of ligand FasL to its receptor Fas triggers apoptosis via the caspase cascade. FasL itself is homotrimeric, and a productive apoptotic signal requires that FasL be oligomerized beyond the homotrimeric state. We generated a series of FasL chimeras by fusing FasL to domains of the Leukemia Inhibitory Factor receptor gp190 which confer homotypic oligomerization, and analyzed the capacity of these soluble chimeras to trigger cell death. We observed that the most efficient FasL chimera, called pFasL, was also the most polymeric, as it reached the size of a dodecamer. Using a cellular model, we investigated the structure-function relationships of the FasL-Fas interactions for our chimeras, and we demonstrated that the Fas-mediated apoptotic signal did not solely rely on ligand-mediated receptor aggregation, but also required a conformational adaptation of the Fas receptor. When injected into mice, pFasL did not trigger liver injury at a dose which displayed anti-tumor activity in a model of human tumor transplanted to immunodeficient animals, suggesting a potential therapeutic use. Therefore, the optimization of the FasL conformation has to be considered for the development of efficient FasL-derived anti-cancer drugs targeting Fas.

Autor: Sophie Daburon - Christel Devaud - Pierre Costet - Aurore Morello - Laure Garrigue-Antar - Mike Maillasson - Nathalie Hargous - D



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