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Migration pattern, actin cytoskeleton organization and response to PI3K-, mTOR-, and Hsp90-inhibition of glioblastoma cells with different invasive capacities

High invasiveness and resistance to chemo- and radiotherapy of glioblastoma multiforme (GBM) make it the most lethal brain tumor. Therefore, new treatment strategies for preventing migration and invasion of GBM cells are needed. Using two different migration assays, Western blotting, conventional an...

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Autores principales: Memmel, Simon, Sisario, Dmitri, Zöller, Caren, Fiedler, Vanessa, Katzer, Astrid, Heiden, Robin, Becker, Nicholas, Eing, Lorenz, Ferreira, Fábio L.R., Zimmermann, Heiko, Sauer, Markus, Flentje, Michael, Sukhorukov, Vladimir L., Djuzenova, Cholpon S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542187/
https://www.ncbi.nlm.nih.gov/pubmed/28424411
http://dx.doi.org/10.18632/oncotarget.16847
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author Memmel, Simon
Sisario, Dmitri
Zöller, Caren
Fiedler, Vanessa
Katzer, Astrid
Heiden, Robin
Becker, Nicholas
Eing, Lorenz
Ferreira, Fábio L.R.
Zimmermann, Heiko
Sauer, Markus
Flentje, Michael
Sukhorukov, Vladimir L.
Djuzenova, Cholpon S.
author_facet Memmel, Simon
Sisario, Dmitri
Zöller, Caren
Fiedler, Vanessa
Katzer, Astrid
Heiden, Robin
Becker, Nicholas
Eing, Lorenz
Ferreira, Fábio L.R.
Zimmermann, Heiko
Sauer, Markus
Flentje, Michael
Sukhorukov, Vladimir L.
Djuzenova, Cholpon S.
author_sort Memmel, Simon
collection PubMed
description High invasiveness and resistance to chemo- and radiotherapy of glioblastoma multiforme (GBM) make it the most lethal brain tumor. Therefore, new treatment strategies for preventing migration and invasion of GBM cells are needed. Using two different migration assays, Western blotting, conventional and super-resolution (dSTORM) fluorescence microscopy we examine the effects of the dual PI3K/mTOR-inhibitor PI-103 alone and in combination with the Hsp90 inhibitor NVP-AUY922 and/or irradiation on the migration, expression of marker proteins, focal adhesions and F-actin cytoskeleton in two GBM cell lines (DK-MG and SNB19) markedly differing in their invasive capacity. Both lines were found to be strikingly different in morphology and migration behavior. The less invasive DK-MG cells maintained a polarized morphology and migrated in a directionally persistent manner, whereas the highly invasive SNB19 cells showed a multipolar morphology and migrated randomly. Interestingly, a single dose of 2 Gy accelerated wound closure in both cell lines without affecting their migration measured by single-cell tracking. PI-103 inhibited migration of DK-MG (p53 wt, PTEN wt) but not of SNB19 (p53 mut, PTEN mut) cells probably due to aberrant reactivation of the PI3K pathway in SNB19 cells treated with PI-103. In contrast, NVP-AUY922 exerted strong anti-migratory effects in both cell lines. Inhibition of cell migration was associated with massive morphological changes and reorganization of the actin cytoskeleton. Our results showed a cell line-specific response to PI3K/mTOR inhibition in terms of GBM cell motility. We conclude that anti-migratory agents warrant further preclinical investigation as potential therapeutics for treatment of GBM.
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spelling pubmed-55421872017-08-07 Migration pattern, actin cytoskeleton organization and response to PI3K-, mTOR-, and Hsp90-inhibition of glioblastoma cells with different invasive capacities Memmel, Simon Sisario, Dmitri Zöller, Caren Fiedler, Vanessa Katzer, Astrid Heiden, Robin Becker, Nicholas Eing, Lorenz Ferreira, Fábio L.R. Zimmermann, Heiko Sauer, Markus Flentje, Michael Sukhorukov, Vladimir L. Djuzenova, Cholpon S. Oncotarget Research Paper High invasiveness and resistance to chemo- and radiotherapy of glioblastoma multiforme (GBM) make it the most lethal brain tumor. Therefore, new treatment strategies for preventing migration and invasion of GBM cells are needed. Using two different migration assays, Western blotting, conventional and super-resolution (dSTORM) fluorescence microscopy we examine the effects of the dual PI3K/mTOR-inhibitor PI-103 alone and in combination with the Hsp90 inhibitor NVP-AUY922 and/or irradiation on the migration, expression of marker proteins, focal adhesions and F-actin cytoskeleton in two GBM cell lines (DK-MG and SNB19) markedly differing in their invasive capacity. Both lines were found to be strikingly different in morphology and migration behavior. The less invasive DK-MG cells maintained a polarized morphology and migrated in a directionally persistent manner, whereas the highly invasive SNB19 cells showed a multipolar morphology and migrated randomly. Interestingly, a single dose of 2 Gy accelerated wound closure in both cell lines without affecting their migration measured by single-cell tracking. PI-103 inhibited migration of DK-MG (p53 wt, PTEN wt) but not of SNB19 (p53 mut, PTEN mut) cells probably due to aberrant reactivation of the PI3K pathway in SNB19 cells treated with PI-103. In contrast, NVP-AUY922 exerted strong anti-migratory effects in both cell lines. Inhibition of cell migration was associated with massive morphological changes and reorganization of the actin cytoskeleton. Our results showed a cell line-specific response to PI3K/mTOR inhibition in terms of GBM cell motility. We conclude that anti-migratory agents warrant further preclinical investigation as potential therapeutics for treatment of GBM. Impact Journals LLC 2017-04-05 /pmc/articles/PMC5542187/ /pubmed/28424411 http://dx.doi.org/10.18632/oncotarget.16847 Text en Copyright: © 2017 Memmel et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Memmel, Simon
Sisario, Dmitri
Zöller, Caren
Fiedler, Vanessa
Katzer, Astrid
Heiden, Robin
Becker, Nicholas
Eing, Lorenz
Ferreira, Fábio L.R.
Zimmermann, Heiko
Sauer, Markus
Flentje, Michael
Sukhorukov, Vladimir L.
Djuzenova, Cholpon S.
Migration pattern, actin cytoskeleton organization and response to PI3K-, mTOR-, and Hsp90-inhibition of glioblastoma cells with different invasive capacities
title Migration pattern, actin cytoskeleton organization and response to PI3K-, mTOR-, and Hsp90-inhibition of glioblastoma cells with different invasive capacities
title_full Migration pattern, actin cytoskeleton organization and response to PI3K-, mTOR-, and Hsp90-inhibition of glioblastoma cells with different invasive capacities
title_fullStr Migration pattern, actin cytoskeleton organization and response to PI3K-, mTOR-, and Hsp90-inhibition of glioblastoma cells with different invasive capacities
title_full_unstemmed Migration pattern, actin cytoskeleton organization and response to PI3K-, mTOR-, and Hsp90-inhibition of glioblastoma cells with different invasive capacities
title_short Migration pattern, actin cytoskeleton organization and response to PI3K-, mTOR-, and Hsp90-inhibition of glioblastoma cells with different invasive capacities
title_sort migration pattern, actin cytoskeleton organization and response to pi3k-, mtor-, and hsp90-inhibition of glioblastoma cells with different invasive capacities
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542187/
https://www.ncbi.nlm.nih.gov/pubmed/28424411
http://dx.doi.org/10.18632/oncotarget.16847
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