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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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Research Letters
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988508/
https://www.ncbi.nlm.nih.gov/pubmed/27282934
http://dx.doi.org/10.1002/1873-3468.12243
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author 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
author_facet 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
author_sort Mutz, Cornelia N.
collection PubMed
description 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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spelling pubmed-49885082016-08-30 EWS‐FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway 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 FEBS Lett Research Letters 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. John Wiley and Sons Inc. 2016-06-21 2016-07 /pmc/articles/PMC4988508/ /pubmed/27282934 http://dx.doi.org/10.1002/1873-3468.12243 Text en © 2016 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Letters
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
EWS‐FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway
title EWS‐FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway
title_full EWS‐FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway
title_fullStr EWS‐FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway
title_full_unstemmed EWS‐FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway
title_short EWS‐FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway
title_sort ews‐fli1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway
topic Research Letters
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988508/
https://www.ncbi.nlm.nih.gov/pubmed/27282934
http://dx.doi.org/10.1002/1873-3468.12243
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