Neuregulin-1 enhances survival of human astrocytic glioma cells
Neuregulin-1 enhances survival of human astrocytic glioma cells
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DOI：
10.1002/glia.20197
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发表时间：
2005-08-15
期刊：
影响因子：
6.2
通讯作者：
Sontheimer, H
中科院分区：
文献类型：
--
作者：
Ritch, PS;Carroll, SL;Sontheimer, H
恶性星形细胞胶质瘤，称为星形细胞瘤，是最常见的成人原发性脑肿瘤。这些肿瘤的特点是无情的增长，往往是耐化疗和放射治疗。肿瘤扩展到周围健康的脑组织会产生严重的，往往是致命的后果。在这项研究中，我们研究的潜力neuregulin-1/erbB受体信号级联有助于这一进程通过调节胶质瘤细胞的生长。使用特异性的erbB受体的抗体，我们证明了erbB 2，erbB 3，和erbB 4受体在人脑胶质瘤活检样本的表达模式。然后我们在一组人脑胶质瘤细胞系中验证受体表达。接下来，我们研究了人脑胶质瘤细胞系中erbB 2和erbB 3受体的状态，发现它们是组成性酪氨酸磷酸化和异源二聚体化的。随后，我们证明，这些相同的细胞系表达膜结合和释放形式的neuregulins，erbB受体配体，这表明可能的自分泌或旁分泌信号网络。此外，我们表明，外源性激活erbB 2和erbB 3受体在U251胶质瘤细胞的重组Nrg-1 β的结果在增强胶质瘤细胞生长的条件下，血清剥夺。这种增强是由于细胞存活率的增加而不是细胞增殖的增加，并且依赖于erbB 2和磷脂酰肌醇-3激酶（PI 3 K）的激活。此外，Nrg-1 β激活凋亡抑制剂Akt，这意味着该激酶在介导神经胶质瘤中的Nrg-1 β效应中可能起作用。这些数据表明，神经胶质瘤细胞可能利用自分泌或旁分泌神经调节素-1/erbB受体信号传导来增强细胞在生长受限的条件下的存活。(c)2005 Wiley-Liss，Inc.
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.