Abstract
BackgroundEpidermal 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.MethodsExpression 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.ResultsEREG 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.ConclusionEREG 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.
Highlights
Epidermal growth factor (EGF) receptors contribute to the development of malignant glioma
Since EREG contributes to the angiogenesis process as well as to tumor metastasis in breast carcinoma models [23], we further considered its possible relationship to IRE1α and to glioma development and analyzed its status in several glioblastoma cell lines and in malignant glioma
We observed that the two transcripts were abundant both in wild type U87 (U87wt) cells and in cells transfected with the empty vector (U87Ctrl cells), whereas ~100-fold (EREG) and 8-fold (HB-EGF) decreases were monitored in cells expressing an IRE1α dominant-negative protein (U87dn cells) (Figure 1a)
Summary
Epidermal growth factor (EGF) receptors contribute to the development of malignant glioma. The moderate efficacy of current clinical approaches underline the need for new therapeutic strategies [1]. Some of these focus on the inhibition of EGF receptors, collectively referred to as the ErbB/HER tyrosine kinase receptor family [2]. Amplification of ErbB1 and alteration of its activity are important contributors to glioma development [3,4]. For these reasons, phase II trials for high-grade gliomas have been targeting ErbB1 by using either humanized antibodies directed against the receptor extracellular domain (cetuximab, trade name Erbitux®), or pharmacological inhibitors of its protein kinase activity (erlotinib, gefinitib) [1,3,4]. The participation of the three others EGF receptors (ErbB2-ErbB4) in glioma progression by deregulation of ErbB signaling networks has been considered [4,5,6,7]
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