EWS-FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway

Ewing sarcoma (ES) is an aggressive pediatric tumor driven by the fusion protein EWS-FLI1. We report that EWS-FLI1 suppresses TDO2-mediated tryptophan (TRP) breakdown in ES cells. Gene expression and metabolite analyses reveal an EWS-FLI1-dependent regulation of TRP metabolism. TRP consumption incre...

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Detalles Bibliográficos
Autores: Mutz, Cornelia N, Schwentner, Raphaela, Kauer, Maximilian O, Katschnig, Anna M, Kromp, Florian, Aryee, Dave N T, Erhardt, Sophie, Goiny, Michel, Alonso, Javier, Fuchs, Dietmar, Kovar, Heinrich
Tipo de recurso: artículo
Fecha de publicación:2016
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/13225
Acceso en línea:http://hdl.handle.net/20.500.12105/13225
Access Level:acceso abierto
Palabra clave:Autocrine Communication
Signal Transduction
Cell Line
Humans
Kynurenine
Oncogene Proteins, Fusion
Proto-Oncogene Protein c-fli-1
RNA-Binding Protein EWS
Receptors, Aryl Hydrocarbon
Tryptophan
Tryptophan Oxygenase
Descripción
Sumario:Ewing sarcoma (ES) is an aggressive pediatric tumor driven by the fusion protein EWS-FLI1. We report that EWS-FLI1 suppresses TDO2-mediated tryptophan (TRP) breakdown in ES cells. Gene expression and metabolite analyses reveal an EWS-FLI1-dependent regulation of TRP metabolism. TRP consumption increased in the absence of EWS-FLI1, resulting in kynurenine and kynurenic acid accumulation, both aryl hydrocarbon receptor (AHR) ligands. Activated AHR binds to the promoter region of target genes. We demonstrate that EWS-FLI1 knockdown results in AHR nuclear translocation and activation. Our data suggest that EWS-FLI1 suppresses autocrine AHR signaling by inhibiting TDO2-catalyzed TRP breakdown.

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