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

大量证据表明，胶质母细胞瘤细胞通过自分泌或旁分泌环释放谷氨酸并利用谷氨酸进行增殖和迁移，钙离子可渗透的AMPA型谷氨酸受体在胶质母细胞瘤的侵袭性生长中起重要作用。在这里，我们发现AMPA受体介导的Ca^<2+>信号通过激活Akt调节胶质母细胞瘤细胞的生长和运动。通过Ca^2+渗透性AMPA受体提供的Ca ^2+使Akt的Ser-473磷酸化，从而促进增殖和迁移。Akt的一种显性负性形式可抑制细胞增殖，并通过过表达Ca^2+渗透性AMPA受体加速细胞迁移。与此相反，Akt的组成型活性形式的引入拯救了肿瘤细胞免于通过GluR 2 cDNA的递送将Ca^2+可渗透的AMPA受体转化为Ca^2+不可渗透的受体而诱导的凋亡。因此，Akt在胶质母细胞瘤细胞中作为AMPA受体介导的Ca^2+信号传导的下游效应物发挥作用。胶质瘤细胞释放的谷氨酸通过Ca^2+可渗透的AMPA受体参与Akt活性，谷氨酸-AMPA-Akt通路的激活有助于人胶质母细胞瘤的高度间变性和侵袭性生长。因此，这种新的途径可能会提供替代的治疗靶点。

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.