期刊
INTERNATIONAL JOURNAL OF CANCER
卷 144, 期 10, 页码 2539-2554出版社
WILEY
DOI: 10.1002/ijc.31985
关键词
glioblastoma; GLAST; EAAT1; glutamate; UCPH-101; STAT3
类别
资金
- Il Fondo di Gio and Associazione Italiana Tumori Cerebrali
- Fondazione IRCCS Istituto Neurologico C. Besta 5X1000 funds
- Fondazione Giovanni Celeghin
- Associazione Italiana per la Ricerca sul Cancro [14323]
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.
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