期刊
CANCER RESEARCH
卷 67, 期 19, 页码 9463-9471出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-07-2034
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资金
- NCI NIH HHS [P50-CA97247, P50 CA097247] Funding Source: Medline
- NINDS NIH HHS [R01 NS052634-03, R01NS052634, R01 NS031234-14A1, R01 NS036692-08, R01 NS031234, R01 NS052634, R01 NS036692, R01-NS31234] Funding Source: Medline
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 x(C)(-), 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 x(C)(-). This inhibition could be overcome by the addition of exogenous glutamate (100 mu mol/L) in the continued presence of the 2, 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 21 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 x(C)- 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 x(C)(-) -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.
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