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

Gregor Auf, Arnaud Jabouille, Maylis Delugin, Sylvaine Guérit, Raphael Pineau, Sophie North, Natalia Platonova, Marlène Maitre, Alexandre Favereaux, Peter Vajkoczy, Masaharu Seno, Andreas Bikfalvi, Dmitri Minchenko, Oleksandr Minchenko, Michel Moenner

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article number597
JournalBMC Cancer
Volume13
DOIs
Publication statusPublished - Dec 13 2013

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Epidermal Growth Factor Receptor
Glioma
Growth
Ribonucleases
Heterografts
Small Interfering RNA
Epiregulin
Intercellular Signaling Peptides and Proteins
Phosphotransferases
Unfolded Protein Response
Endoplasmic Reticulum Stress
Blocking Antibodies
JNK Mitogen-Activated Protein Kinases
Glioblastoma
Anti-Idiotypic Antibodies
Neoplasms
Cell Culture Techniques
Cell Proliferation
Ligands
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

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.

In: BMC Cancer, Vol. 13, 597, 13.12.2013.

Research output: Contribution to journalArticle

Auf, G, Jabouille, A, Delugin, M, Guérit, S, Pineau, R, North, S, Platonova, N, Maitre, M, Favereaux, A, Vajkoczy, P, Seno, M, Bikfalvi, A, Minchenko, D, Minchenko, O & Moenner, M 2013, 'High epiregulin expression in human U87 glioma cells relies on IRE1α and promotes autocrine growth through EGF receptor', BMC Cancer, vol. 13, 597. https://doi.org/10.1186/1471-2407-13-597
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. In: BMC Cancer. 2013 ; Vol. 13.
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abstract = "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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AU - Auf, Gregor

AU - Jabouille, Arnaud

AU - Delugin, Maylis

AU - Guérit, Sylvaine

AU - Pineau, Raphael

AU - North, Sophie

AU - Platonova, Natalia

AU - Maitre, Marlène

AU - Favereaux, Alexandre

AU - Vajkoczy, Peter

AU - Seno, Masaharu

AU - Bikfalvi, Andreas

AU - Minchenko, Dmitri

AU - Minchenko, Oleksandr

AU - Moenner, Michel

PY - 2013/12/13

Y1 - 2013/12/13

N2 - 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.

AB - 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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