Altered function of the glutamate aspartate transporter GLAST in glioblastoma

Pellegatta, S.; Corbetta, C.; Di Ianna, N.; Bruzzone, M. G.; Patane, M.; Pollo, B.; Cantini, G.; Cominelli, M.; Zucca, I.; Pisati, F.; Poliani, P. L.; Finocchiaro, G.

doi:10.1101/287623

bioRxiv · 10.1101/287623

Altered function of the glutamate aspartate transporter GLAST in glioblastoma

Pellegatta, S.·Corbetta, C.·Di Ianna, N.·Bruzzone, M. G.·Patane, M.·Pollo, B.·Cantini, G.·Cominelli, M.·Zucca, I.·Pisati, F.·Poliani, P. L.·Finocchiaro, G.

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Abstract

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. Despite their GLAST expression, GBM stem-like cells (GSCs) released rather than took 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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Pellegatta, S., Corbetta, C., Di Ianna, N., Bruzzone, M. G., Patane, M., Pollo, B., Cantini, G., Cominelli, M., Zucca, I., Pisati, F., Poliani, P. L., Finocchiaro, G.. 2018-03-23. Altered function of the glutamate aspartate transporter GLAST in glioblastoma. https://doi.org/10.1101/287623

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