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The tubulin inhibitor MG-2477 induces autophagy-regulated cell death, ROS accumulation and activation of FOXO3 in neuroblastoma

Neuroblastoma is the most frequent extra-cranial solid tumor in children with still high mortality in stage M. Here we studied the tubulin-inhibitor MG-2477 as a possible therapeutic agent for neuroblastoma therapy and uncovered that MG-2477 induces death in neuroblastoma cells independent of PKB-ac...

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Autores principales: Hagenbuchner, Judith, Lungkofler, Lorena, Kiechl-Kohlendorfer, Ursula, Viola, Giampietro, Ferlin, Maria Grazia, Ausserlechner, Michael J., Obexer, Petra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458265/
https://www.ncbi.nlm.nih.gov/pubmed/28415610
http://dx.doi.org/10.18632/oncotarget.16434
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author Hagenbuchner, Judith
Lungkofler, Lorena
Kiechl-Kohlendorfer, Ursula
Viola, Giampietro
Ferlin, Maria Grazia
Ausserlechner, Michael J.
Obexer, Petra
author_facet Hagenbuchner, Judith
Lungkofler, Lorena
Kiechl-Kohlendorfer, Ursula
Viola, Giampietro
Ferlin, Maria Grazia
Ausserlechner, Michael J.
Obexer, Petra
author_sort Hagenbuchner, Judith
collection PubMed
description Neuroblastoma is the most frequent extra-cranial solid tumor in children with still high mortality in stage M. Here we studied the tubulin-inhibitor MG-2477 as a possible therapeutic agent for neuroblastoma therapy and uncovered that MG-2477 induces death in neuroblastoma cells independent of PKB-activation status and stage. MG-2477 triggers within 30 minutes extensive autophagosome-formation that finally leads to cell death associated with mitotic catastrophe. Autophagy is critical for MG-2477-induced death and is regulated by the BH3-only protein PMAIP1/NOXA which sequesters the anti-apoptotic BCL2-protein BCLXL and thereby displaces and activates the autophagy-regulator BECN1/beclin1. Knockdown of NOXA or overexpression of its pro-survival binding partners MCL1 and BCLXL counteracts MG-2477-induced cell death. MG-2477 also rapidly induces the repression of the anti-apoptotic protein Survivin, which promotes autophagy and cell death. We further observed the accumulation of reactive oxygen species (ROS) that triggers autophagy induction suggesting a change of the PI3 kinase-III/BECN1 complex and activates the transcription factor FOXO3, which contributes to final cell death induction. The combined data suggest that MG-2477 induces a sequential process of ROS-accumulation, autophagy and FOXO3-activation that leads to cell death in neuroblastoma cells.
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spelling pubmed-54582652017-06-08 The tubulin inhibitor MG-2477 induces autophagy-regulated cell death, ROS accumulation and activation of FOXO3 in neuroblastoma Hagenbuchner, Judith Lungkofler, Lorena Kiechl-Kohlendorfer, Ursula Viola, Giampietro Ferlin, Maria Grazia Ausserlechner, Michael J. Obexer, Petra Oncotarget Research Paper Neuroblastoma is the most frequent extra-cranial solid tumor in children with still high mortality in stage M. Here we studied the tubulin-inhibitor MG-2477 as a possible therapeutic agent for neuroblastoma therapy and uncovered that MG-2477 induces death in neuroblastoma cells independent of PKB-activation status and stage. MG-2477 triggers within 30 minutes extensive autophagosome-formation that finally leads to cell death associated with mitotic catastrophe. Autophagy is critical for MG-2477-induced death and is regulated by the BH3-only protein PMAIP1/NOXA which sequesters the anti-apoptotic BCL2-protein BCLXL and thereby displaces and activates the autophagy-regulator BECN1/beclin1. Knockdown of NOXA or overexpression of its pro-survival binding partners MCL1 and BCLXL counteracts MG-2477-induced cell death. MG-2477 also rapidly induces the repression of the anti-apoptotic protein Survivin, which promotes autophagy and cell death. We further observed the accumulation of reactive oxygen species (ROS) that triggers autophagy induction suggesting a change of the PI3 kinase-III/BECN1 complex and activates the transcription factor FOXO3, which contributes to final cell death induction. The combined data suggest that MG-2477 induces a sequential process of ROS-accumulation, autophagy and FOXO3-activation that leads to cell death in neuroblastoma cells. Impact Journals LLC 2017-03-22 /pmc/articles/PMC5458265/ /pubmed/28415610 http://dx.doi.org/10.18632/oncotarget.16434 Text en Copyright: © 2017 Hagenbuchner et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Hagenbuchner, Judith
Lungkofler, Lorena
Kiechl-Kohlendorfer, Ursula
Viola, Giampietro
Ferlin, Maria Grazia
Ausserlechner, Michael J.
Obexer, Petra
The tubulin inhibitor MG-2477 induces autophagy-regulated cell death, ROS accumulation and activation of FOXO3 in neuroblastoma
title The tubulin inhibitor MG-2477 induces autophagy-regulated cell death, ROS accumulation and activation of FOXO3 in neuroblastoma
title_full The tubulin inhibitor MG-2477 induces autophagy-regulated cell death, ROS accumulation and activation of FOXO3 in neuroblastoma
title_fullStr The tubulin inhibitor MG-2477 induces autophagy-regulated cell death, ROS accumulation and activation of FOXO3 in neuroblastoma
title_full_unstemmed The tubulin inhibitor MG-2477 induces autophagy-regulated cell death, ROS accumulation and activation of FOXO3 in neuroblastoma
title_short The tubulin inhibitor MG-2477 induces autophagy-regulated cell death, ROS accumulation and activation of FOXO3 in neuroblastoma
title_sort tubulin inhibitor mg-2477 induces autophagy-regulated cell death, ros accumulation and activation of foxo3 in neuroblastoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458265/
https://www.ncbi.nlm.nih.gov/pubmed/28415610
http://dx.doi.org/10.18632/oncotarget.16434
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