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Analysis of the mechanism of invasive growth of human glioblastomas. PART II

人胶质母细胞瘤侵袭性生长机制分析。

基本信息

批准号：
17390391
负责人：
ISHIUCHI Shogo
金额：
$ 10.18万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390391/
关键词：
glioblastoma invasive growth signal transduction glutamate AMPA antagonists

项目摘要

Evidence has accumulated that glioblastoma cells release and exploit glutamate for proliferation and migration by autocrine or paracrine loops.Ca^<2+>-permeable-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors are important role for the invasive growth of human glioblastomas. Here we show that Ca^<2+> signaling mediated by AMPA receptors regulates the growth and motility of glioblastoma cells via activation of Akt. Ca^<2+> supplied through Ca^<2+>-permeable AMPA receptors phosphorylated Akt at Ser-473, thereby facilitating proliferation and mobility. A dominant negative form of Akt inhibited proliferation and migration accelerated by overexpression of Ca^<2+>-permeable AMPA receptors. In contrast, introduction of a constitutively active form of Akt rescued tumor cells from apoptosis induced by the conversion of Ca^<2+>-permeable AMPA receptors to Ca^<2+>-impermeable receptors by the delivery of GluR2 cDNA.Therefore, Akt functions as a downstream effector for Ca^<2+>-signaling mediated by AMPA receptors in glioblastoma cells. Glutamate released by glioma cells is involved in Akt activity through Ca^<2+>-permeable AMPA receptors and the activation of Glutamate-AMPA-Akt pathway contributes to the high degree of anaplasia and invasive growth of human glioblastoma. Thus this novel pathway might give alternative therapeutic target.

越来越多的证据表明，胶质母细胞瘤细胞通过自分泌或旁分泌loops.Ca^&lt；2+&gt；-permeable-amino-3-hydroxy-5-methyl-4-isoxazolepropionate(Ampa)型谷氨酸受体释放谷氨酸，并利用谷氨酸进行增殖和迁移，对胶质母细胞瘤的侵袭性生长具有重要作用。在此，我们证明了AMPA受体介导的钙信号通路通过激活Akt来调节胶质母细胞瘤细胞的生长和运动。通过钙离子通透性AMPA受体提供的钙离子使Akt在Ser-473处磷酸化，从而促进细胞的增殖和运动。AKT的显性负性形式可通过钙离子通透性AMPA受体的过度表达而抑制细胞的增殖和迁移。相反，在胶质母细胞瘤细胞中，引入一种结构性活性形式的Akt可以使肿瘤细胞免于通过GluR2 cDNAs将钙离子通透性的AMPA受体转化为非渗透性的钙离子受体而诱导的细胞凋亡。因此，Akt在胶质母细胞瘤细胞中作为AMPA受体介导的钙离子信号的下游效应器。胶质瘤细胞释放的谷氨酸通过钙离子通透性AMPA受体参与Akt活性，谷氨酸-AMPA-Akt途径的激活与胶质母细胞瘤的高度间变和侵袭性生长有关。因此，这一新途径可能成为新的治疗靶点。