title: High epiregulin expression in human U87 glioma cells relies on IRE1α and promotes autocrine growth through EGF receptor.
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.
  
  
  CONCLUSIONS
  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.
authors: Gregor
authors: G
authors: Auf
authors: Arnaud
authors: A
authors: Jabouille
authors: Maylis
authors: M
authors: Delugin
authors: Sylvaine
authors: S
authors: Guérit
authors: Raphael
authors: R
authors: Pineau
authors: Sophie
authors: S
authors: North
authors: Natalia
authors: N
authors: Platonova
authors: Marlène
authors: M
authors: Maitre
authors: Alexandre
authors: A
authors: Favereaux
authors: Peter
authors: P
authors: Vajkoczy
authors: Masaharu
authors: M
authors: Seno
authors: Andreas
authors: A
authors: Bikfalvi
authors: Dmitri
authors: D
authors: Minchenko
authors: Inserm, LAMC, UMR 1029, Talence F-33400, France. ominchenko@yahoo.com.
authors: Oleksandr
authors: O
authors: Minchenko
authors: Michel
authors: M
authors: Moenner
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D019898:Autocrine Communication; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D000068818:Cetuximab; D004722:Endoribonucleases / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066260:Epiregulin; D066246:ErbB Receptors / Q000378:metabolism*; D015870:Gene Expression; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000873:Anthracenes; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C587880:EREG protein, human; D066260:Epiregulin; C587881:Ereg protein, mouse; C432165:pyrazolanthrone; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases; D000068818:Cetuximab