Analysis of the mechanism of invasive growth of human glioblastomas

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Recent studies show that Ca^<2+>-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors play an important role in the growth of glioblastomas. However, the signaling pathway controlling the proliferation of glioblastoma cells is poorly understood. Protein kinase B/Akt has a critical role in tumorigenesis and can enhance proliferation and inhibit apoptosis in cancer cells. Here we show that Ca^<2+>-signaling mediated by AMPA receptors regulates the motility and growth of glioma cells through the activation of Akt. Ca^<2+> supplied through the Ca^<2+>-permeable AMPA receptors phosphorylated Akt at Ser 473, thereby facilitating proliferation as well as mobility. A dominant negative form of Akt inhibits the 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 their conversion to Ca^<2+>-impermeable receptors by adenovirus-mediated transfer of the GluR2 cDNA. Thus Akt functions as a downstream effector in Ca^<2+>-signaling by AMPA receptors and this pathway may be a novel target in the treatment of glioblastomas.