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
BMC Cancer. 2013-12-01; 13(1):
DOI: 10.1186/1471-2407-13-597

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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

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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