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Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation

Glioblastoma (GBM) is the most common and malignant type of primary brain tumor and associated with a devastating prognosis. Signal transducer and activator of transcription number 3 (STAT3) is an important pathogenic factor in GBM and can be specifically inhibited with Stattic. Metformin inhibits G...

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Autores principales: Leidgens, Verena, Proske, Judith, Rauer, Lisa, Moeckel, Sylvia, Renner, Kathrin, Bogdahn, Ulrich, Riemenschneider, Markus J., Proescholdt, Martin, Vollmann-Zwerenz, Arabel, Hau, Peter, Seliger, Corinna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352398/
https://www.ncbi.nlm.nih.gov/pubmed/28030813
http://dx.doi.org/10.18632/oncotarget.14159
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author Leidgens, Verena
Proske, Judith
Rauer, Lisa
Moeckel, Sylvia
Renner, Kathrin
Bogdahn, Ulrich
Riemenschneider, Markus J.
Proescholdt, Martin
Vollmann-Zwerenz, Arabel
Hau, Peter
Seliger, Corinna
author_facet Leidgens, Verena
Proske, Judith
Rauer, Lisa
Moeckel, Sylvia
Renner, Kathrin
Bogdahn, Ulrich
Riemenschneider, Markus J.
Proescholdt, Martin
Vollmann-Zwerenz, Arabel
Hau, Peter
Seliger, Corinna
author_sort Leidgens, Verena
collection PubMed
description Glioblastoma (GBM) is the most common and malignant type of primary brain tumor and associated with a devastating prognosis. Signal transducer and activator of transcription number 3 (STAT3) is an important pathogenic factor in GBM and can be specifically inhibited with Stattic. Metformin inhibits GBM cell proliferation and migration. Evidence from other tumor models suggests that metformin inhibits STAT3, but there is no specific data on brain tumor initiating cells (BTICs). We explored proliferation and migration of 7 BTICs and their differentiated counterparts (TCs) after treatment with Stattic, metformin or the combination thereof. Invasion was measured in situ on organotypic brain slice cultures. Protein expression of phosphorylated and total STAT3, as well as AMPK and mTOR signaling were explored using Western blot. To determine functional relevance of STAT3 inhibition by Stattic and metformin, we performed a stable knock-in of STAT3 in selected BTICs. Inhibition of STAT3 with Stattic reduced proliferation in all BTICs, but only in 4 out of 7 TCs. Migration and invasion were equally inhibited in BTICs and TCs. Treatment with metformin reduced STAT3-phosphorylation in all investigated BTICs and TCs. Combined treatment with Stattic and metformin led to significant additive effects on BTIC proliferation, but not migration or invasion. No additive effects on TCs could be detected. Stable STAT3 knock-in partly attenuated the effects of Stattic and metformin on BTICs. In conclusion, metformin was found to inhibit STAT3-phosphorylation in BTICs and TCs. Combined specific and unspecific inhibition of STAT3 might represent a promising new strategy in the treatment of glioblastoma.
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spelling pubmed-53523982017-04-14 Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation Leidgens, Verena Proske, Judith Rauer, Lisa Moeckel, Sylvia Renner, Kathrin Bogdahn, Ulrich Riemenschneider, Markus J. Proescholdt, Martin Vollmann-Zwerenz, Arabel Hau, Peter Seliger, Corinna Oncotarget Research Paper Glioblastoma (GBM) is the most common and malignant type of primary brain tumor and associated with a devastating prognosis. Signal transducer and activator of transcription number 3 (STAT3) is an important pathogenic factor in GBM and can be specifically inhibited with Stattic. Metformin inhibits GBM cell proliferation and migration. Evidence from other tumor models suggests that metformin inhibits STAT3, but there is no specific data on brain tumor initiating cells (BTICs). We explored proliferation and migration of 7 BTICs and their differentiated counterparts (TCs) after treatment with Stattic, metformin or the combination thereof. Invasion was measured in situ on organotypic brain slice cultures. Protein expression of phosphorylated and total STAT3, as well as AMPK and mTOR signaling were explored using Western blot. To determine functional relevance of STAT3 inhibition by Stattic and metformin, we performed a stable knock-in of STAT3 in selected BTICs. Inhibition of STAT3 with Stattic reduced proliferation in all BTICs, but only in 4 out of 7 TCs. Migration and invasion were equally inhibited in BTICs and TCs. Treatment with metformin reduced STAT3-phosphorylation in all investigated BTICs and TCs. Combined treatment with Stattic and metformin led to significant additive effects on BTIC proliferation, but not migration or invasion. No additive effects on TCs could be detected. Stable STAT3 knock-in partly attenuated the effects of Stattic and metformin on BTICs. In conclusion, metformin was found to inhibit STAT3-phosphorylation in BTICs and TCs. Combined specific and unspecific inhibition of STAT3 might represent a promising new strategy in the treatment of glioblastoma. Impact Journals LLC 2016-12-24 /pmc/articles/PMC5352398/ /pubmed/28030813 http://dx.doi.org/10.18632/oncotarget.14159 Text en Copyright: © 2017 Leidgens 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Leidgens, Verena
Proske, Judith
Rauer, Lisa
Moeckel, Sylvia
Renner, Kathrin
Bogdahn, Ulrich
Riemenschneider, Markus J.
Proescholdt, Martin
Vollmann-Zwerenz, Arabel
Hau, Peter
Seliger, Corinna
Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation
title Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation
title_full Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation
title_fullStr Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation
title_full_unstemmed Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation
title_short Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation
title_sort stattic and metformin inhibit brain tumor initiating cells by reducing stat3-phosphorylation
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352398/
https://www.ncbi.nlm.nih.gov/pubmed/28030813
http://dx.doi.org/10.18632/oncotarget.14159
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