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Altered function of the glutamate–aspartate transporter GLAST, a potential therapeutic target in glioblastoma
Author(s) -
Corbetta Cristina,
Di Ianni Natalia,
Bruzzone Maria Grazia,
Patanè Monica,
Pollo Bianca,
Cantini Gabriele,
Cominelli Manuela,
Zucca Ileana,
Pisati Federica,
Poliani Pietro Luigi,
Finocchiaro Gaetano,
Pellegatta Serena
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31985
Subject(s) - glutamate receptor , glioma , glutamate aspartate transporter , cancer research , apoptosis , glioblastoma , astrocyte , biology , transporter , chemistry , endocrinology , central nervous system , excitatory amino acid transporter , biochemistry , gene , receptor
In glioma patients, high levels of glutamate can cause brain edema and seizures. GLAST, a glutamate–aspartate transporter expressed by astrocytes with a role in glutamate uptake, is highly expressed on the plasma membrane of glioblastoma (GBM) cells, and its expression significantly correlates with shortened patient survival. Here, it was demonstrated that inhibition of GLAST expression limited the progression and invasion of GBM xenografts. Magnetic resonance spectroscopy was used to measure glutamate in GLAST‐expressing gliomas showing that these tumors exhibit increased glutamate concentration compared to GLAST‐depleted glioma. Despite their GLAST expression, GBM stem‐like cells (GSCs) released rather than taking up glutamate due to their lack of Na+/K+‐ATPase. Overexpression of Na+/K+‐ATPase in these cells restored glutamate uptake and induced apoptosis. The therapeutic relevance of targeting GLAST in gliomas was assessed using the inhibitor UCPH‐101. In glioma‐bearing mice, a single intratumoral injection of UCPH‐101 significantly increased survival by decreasing GLAST expression and inducing apoptosis. Thus, GLAST has a novel role in GBM that appears to have crucial relevance in glutamate trafficking and may thus be a new therapeutic target.