title: Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation.
abstract: Evidence has been accumulated that glioblastoma cells release and exploit glutamate for proliferation and migration by autocrine or paracrine loops through Ca2+-permeable AMPA-type glutamate receptors. Here, we show that Ca2+ signaling mediated by AMPA receptor regulates the growth and motility of glioblastoma cells via activation of Akt. Ca2+ supplied through Ca2+-permeable AMPA receptor phosphorylated Akt at Ser-473, thereby facilitating proliferation and mobility. A dominant-negative form of Akt inhibited cell proliferation and migration accelerated by overexpression of Ca2+-permeable AMPA receptor. In contrast, introduction of a constitutively active form of Akt rescued tumor cells from apoptosis induced by the conversion of Ca2+-permeable AMPA receptor to Ca2+-impermeable receptors by the delivery of GluR2 cDNA. Therefore, Akt functions as downstream effectors for Ca2+-signaling mediated by AMPA receptor in glioblastoma cells. The activation of the glutamate-AMPA receptor-Akt pathway may contribute to the high degree of anaplasia and invasive growth of human glioblastoma. This novel pathway might give an alternative therapeutic target.
authors.affiliation: Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan. ishogo@showa.gunma-u.ac.jp
authors.forename: Shogo
authors.initials: S
authors.lastname: Ishiuchi
authors.forename: Yukari
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sugawara
authors.forename: Masanori
authors.initials: M
authors.lastname: Aihara
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ohtani
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Saito
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tsuzuki
authors.forename: Haruo
authors.initials: H
authors.lastname: Okado
authors.forename: Akiko
authors.initials: A
authors.lastname: Miwa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakazato
authors.forename: Seiji
authors.initials: S
authors.lastname: Ozawa
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics; D049109:Cell Proliferation; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010539:Permeability; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D018091:Receptors, AMPA; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium