Journal
GLIA
Volume 51, Issue 3, Pages 217-228Publisher
WILEY
DOI: 10.1002/glia.20197
Keywords
erbB2; erbB3; apoptosis; PI3K; Akt
Categories
Funding
- NCI NIH HHS [P50CA97247, P50 CA097247, P50 CA097247-010003] Funding Source: Medline
- NINDS NIH HHS [R01 NS036692-05A1, R01-NS36692, R01 NS036692-06, R01 NS036692] Funding Source: Medline
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Malignant astrocytic gliomas, referred to as astrocytomas, represent the most commonly diagnosed adult primary brain tumor. These tumors are characterized by unrelenting growth that is often resistant to chemotherapy and radiation therapy. Tumor expansion into the healthy surrounding brain tissue produces severe and often fatal consequences. In this study, we examine the potential for the neuregulin-1/erbB receptor signaling cascade to contribute to this process by modulating glioma cell growth. Using antibodies specific for the erbB receptors, we demonstrate the expression patterns for the erbB2, erbB3, and erbB4 receptors in human glioma biopsy samples. We then veri receptor expression in a panel of human glioma cell lines. Next, we investigate the status of the erbB2 and erbB3 receptors in the human glioma cell lines and find that they are constitutively tyrosine-phosphorylated and heterodimerized. Subsequently, we demonstrate that theses same cell lines express membrane bound and released forms of neuregulins, the erbB receptor ligands, suggesting a possible autocrine or paracrine signaling network. Furthermore, we show that exogenous activation of erbB2 and erbB3 receptors in U251 glioma cells by recombinant Nrg-1 beta results in enhanced glioma cell growth under conditions of serum-deprivation. This enhancement is due to an increase in cell survival rather than an increase in cell proliferation and is dependent on the activation of erbB2 and phosphatidylinositol-3 kinase (PI3K). Moreover, Nrg-1 beta activates an inhibitor of apoptosis, Akt, implying a possible role for this kinase in mediating Nrg-1 beta effects in gliomas. This data suggests that glioma cells may use autocrine or paracrine neuregulin-1/erbB receptor signaling to enhance cell survival under conditions where growth would otherwise be limited. (c) 2005 Wiley-Liss, Inc.
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