title: Autocrine glutamate signaling promotes glioma cell invasion.
abstract: Malignant gliomas have been shown to release glutamate, which kills surrounding brain cells, creating room for tumor expansion. This glutamate release occurs primarily via system xC, a Na+-independent cystine-glutamate exchanger. We show here, in addition, that the released glutamate acts as an essential autocrine/paracrine signal that promotes cell invasion. Specifically, chemotactic invasion and scrape motility assays each show dose-dependent inhibition of cell migration when glutamate release was inhibited using either S-(4)-CPG or sulfasalazine, both potent blockers of system xC. This inhibition could be overcome by the addition of exogenous glutamate (100 micromol/L) in the continued presence of the inhibitors. Migration/invasion was also inhibited when Ca2+-permeable alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPA-R) were blocked using GYKI or Joro spider toxin, whereas CNQX was ineffective. Ca2+ imaging experiments show that the released glutamate activates Ca2+-permeable AMPA-R and induces intracellular Ca2+ oscillations that are essential for cell migration. Importantly, glioma cells release glutamate in sufficient quantities to activate AMPA-Rs on themselves or neighboring cells, thus acting in an autocrine and/or paracrine fashion. System xC and the appropriate AMPA-R subunits are expressed in all glioma cell lines, patient-derived glioma cells, and acute patient biopsies investigated. Furthermore, animal studies in which human gliomas were xenographed into scid mice show that chronic inhibition of system xC-mediated glutamate release leads to smaller and less invasive tumors compared with saline-treated controls. These data suggest that glioma invasion is effectively disrupted by inhibiting an autocrine glutamate signaling loop with a clinically approved candidate drug, sulfasalazine, already in hand.
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Lyons
authors.forename: W Joon
authors.initials: WJ
authors.lastname: Chung
authors.forename: Amy K
authors.initials: AK
authors.lastname: Weaver
authors.forename: Toyin
authors.initials: T
authors.lastname: Ogunrinu
authors.forename: Harald
authors.initials: H
authors.lastname: Sontheimer
mesh_terms: D027182:Amino Acid Transport System y+ / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011897:Random Allocation; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D012460:Sulfasalazine / Q000494:pharmacology
chemical_list: D027182:Amino Acid Transport System y+; D018091:Receptors, AMPA; C118895:SLC7A11 protein, human; D018698:Glutamic Acid; D012460:Sulfasalazine; D002118:Calcium