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

已有证据表明，胶质母细胞瘤细胞通过自分泌或旁分泌环释放并利用谷氨酸进行增殖和迁移。Ca^2-可渗透性氨基-3-羟基-5-甲基-4-异恶唑丙酸酯(AMPA)型谷氨酸受体在人胶质母细胞瘤的侵袭性生长中发挥重要作用。在此，我们表明AMPA受体介导的Ca^2信号传导通过Akt的激活调节胶质母细胞瘤细胞的生长和运动。通过Ca ^ 2 -可渗透的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的显性失活形式抑制由Ca 2+ -渗透性AMPA受体的过度表达加速的增殖和迁移。相反，引入组成型活性形式的Akt可挽救肿瘤细胞免于因Ca^2-渗透性AMPA受体通过递送GluR2 cDNA而转化为Ca^2-不可渗透性受体而诱导的细胞凋亡。因此，Akt在胶质母细胞瘤细胞中充当由AMPA受体介导的Ca^2-信号传导的下游效应子。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，并且谷氨酸-AMPA-Akt途径的激活有助于人胶质母细胞瘤的高度退变和侵袭性生长。因此，这种新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.