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High epiregulin expression in human U87 glioma cells relies on IRE1α and promotes autocrine growth through EGF receptor

BACKGROUND: Epidermal growth factor (EGF) receptors contribute to the development of malignant glioma. Here we considered the possible implication of the EGFR ligand epiregulin (EREG) in glioma development in relation to the activity of the unfolded protein response (UPR) sensor IRE1α. We also exami...

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Autores principales: Auf, Gregor, Jabouille, Arnaud, Delugin, Maylis, Guérit, Sylvaine, Pineau, Raphael, North, Sophie, Platonova, Natalia, Maitre, Marlène, Favereaux, Alexandre, Vajkoczy, Peter, Seno, Masaharu, Bikfalvi, Andreas, Minchenko, Dmitri, Minchenko, Oleksandr, Moenner, Michel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3878670/
https://www.ncbi.nlm.nih.gov/pubmed/24330607
http://dx.doi.org/10.1186/1471-2407-13-597
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author Auf, Gregor
Jabouille, Arnaud
Delugin, Maylis
Guérit, Sylvaine
Pineau, Raphael
North, Sophie
Platonova, Natalia
Maitre, Marlène
Favereaux, Alexandre
Vajkoczy, Peter
Seno, Masaharu
Bikfalvi, Andreas
Minchenko, Dmitri
Minchenko, Oleksandr
Moenner, Michel
author_facet Auf, Gregor
Jabouille, Arnaud
Delugin, Maylis
Guérit, Sylvaine
Pineau, Raphael
North, Sophie
Platonova, Natalia
Maitre, Marlène
Favereaux, Alexandre
Vajkoczy, Peter
Seno, Masaharu
Bikfalvi, Andreas
Minchenko, Dmitri
Minchenko, Oleksandr
Moenner, Michel
author_sort Auf, Gregor
collection PubMed
description BACKGROUND: Epidermal growth factor (EGF) receptors contribute to the development of malignant glioma. Here we considered the possible implication of the EGFR ligand epiregulin (EREG) in glioma development in relation to the activity of the unfolded protein response (UPR) sensor IRE1α. We also examined EREG status in several glioblastoma cell lines and in malignant glioma. METHODS: Expression and biological properties of EREG were analyzed in human glioma cells in vitro and in human tumor xenografts with regard to the presence of ErbB proteins and to the blockade of IRE1α. Inactivation of IRE1α was achieved by using either the dominant-negative strategy or siRNA-mediated knockdown. RESULTS: EREG was secreted in high amounts by U87 cells, which also expressed its cognate EGF receptor (ErbB1). A stimulatory autocrine loop mediated by EREG was evidenced by the decrease in cell proliferation using specific blocking antibodies directed against either ErbB1 (cetuximab) or EREG itself. In comparison, anti-ErbB2 antibodies (trastuzumab) had no significant effect. Inhibition of IRE1α dramatically reduced EREG expression both in cell culture and in human xenograft tumor models. The high-expression rate of EREG in U87 cells was therefore linked to IRE1α, although being modestly affected by chemical inducers of the endoplasmic reticulum stress. In addition, IRE1-mediated production of EREG did not depend on IRE1 RNase domain, as neither the selective dominant-negative invalidation of the RNase activity (IRE1 kinase active) nor the siRNA-mediated knockdown of XBP1 had significant effect on EREG expression. Finally, chemical inhibition of c-Jun N-terminal kinases (JNK) using the SP600125 compound reduced the ability of cells to express EREG, demonstrating a link between the growth factor production and JNK activation under the dependence of IRE1α. CONCLUSION: EREG may contribute to glioma progression under the control of IRE1α, as exemplified here by the autocrine proliferation loop mediated in U87 cells by the growth factor through ErbB1.
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spelling pubmed-38786702014-01-03 High epiregulin expression in human U87 glioma cells relies on IRE1α and promotes autocrine growth through EGF receptor Auf, Gregor Jabouille, Arnaud Delugin, Maylis Guérit, Sylvaine Pineau, Raphael North, Sophie Platonova, Natalia Maitre, Marlène Favereaux, Alexandre Vajkoczy, Peter Seno, Masaharu Bikfalvi, Andreas Minchenko, Dmitri Minchenko, Oleksandr Moenner, Michel BMC Cancer Research Article BACKGROUND: Epidermal growth factor (EGF) receptors contribute to the development of malignant glioma. Here we considered the possible implication of the EGFR ligand epiregulin (EREG) in glioma development in relation to the activity of the unfolded protein response (UPR) sensor IRE1α. We also examined EREG status in several glioblastoma cell lines and in malignant glioma. METHODS: Expression and biological properties of EREG were analyzed in human glioma cells in vitro and in human tumor xenografts with regard to the presence of ErbB proteins and to the blockade of IRE1α. Inactivation of IRE1α was achieved by using either the dominant-negative strategy or siRNA-mediated knockdown. RESULTS: EREG was secreted in high amounts by U87 cells, which also expressed its cognate EGF receptor (ErbB1). A stimulatory autocrine loop mediated by EREG was evidenced by the decrease in cell proliferation using specific blocking antibodies directed against either ErbB1 (cetuximab) or EREG itself. In comparison, anti-ErbB2 antibodies (trastuzumab) had no significant effect. Inhibition of IRE1α dramatically reduced EREG expression both in cell culture and in human xenograft tumor models. The high-expression rate of EREG in U87 cells was therefore linked to IRE1α, although being modestly affected by chemical inducers of the endoplasmic reticulum stress. In addition, IRE1-mediated production of EREG did not depend on IRE1 RNase domain, as neither the selective dominant-negative invalidation of the RNase activity (IRE1 kinase active) nor the siRNA-mediated knockdown of XBP1 had significant effect on EREG expression. Finally, chemical inhibition of c-Jun N-terminal kinases (JNK) using the SP600125 compound reduced the ability of cells to express EREG, demonstrating a link between the growth factor production and JNK activation under the dependence of IRE1α. CONCLUSION: EREG may contribute to glioma progression under the control of IRE1α, as exemplified here by the autocrine proliferation loop mediated in U87 cells by the growth factor through ErbB1. BioMed Central 2013-12-13 /pmc/articles/PMC3878670/ /pubmed/24330607 http://dx.doi.org/10.1186/1471-2407-13-597 Text en Copyright © 2013 Auf et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Auf, Gregor
Jabouille, Arnaud
Delugin, Maylis
Guérit, Sylvaine
Pineau, Raphael
North, Sophie
Platonova, Natalia
Maitre, Marlène
Favereaux, Alexandre
Vajkoczy, Peter
Seno, Masaharu
Bikfalvi, Andreas
Minchenko, Dmitri
Minchenko, Oleksandr
Moenner, Michel
High epiregulin expression in human U87 glioma cells relies on IRE1α and promotes autocrine growth through EGF receptor
title High epiregulin expression in human U87 glioma cells relies on IRE1α and promotes autocrine growth through EGF receptor
title_full High epiregulin expression in human U87 glioma cells relies on IRE1α and promotes autocrine growth through EGF receptor
title_fullStr High epiregulin expression in human U87 glioma cells relies on IRE1α and promotes autocrine growth through EGF receptor
title_full_unstemmed High epiregulin expression in human U87 glioma cells relies on IRE1α and promotes autocrine growth through EGF receptor
title_short High epiregulin expression in human U87 glioma cells relies on IRE1α and promotes autocrine growth through EGF receptor
title_sort high epiregulin expression in human u87 glioma cells relies on ire1α and promotes autocrine growth through egf receptor
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3878670/
https://www.ncbi.nlm.nih.gov/pubmed/24330607
http://dx.doi.org/10.1186/1471-2407-13-597
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