Altered function of the glutamate–aspartate transporter GLAST, a potential therapeutic target in glioblastoma

Cristina Corbetta, Natalia Di Ianni, Maria Grazia Bruzzone, Monica Patanè, Bianca Pollo, Gabriele Cantini, Manuela Cominelli, Ileana Zucca, Federica Pisati, Pietro Luigi Poliani, Gaetano Finocchiaro, Serena Pellegatta

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
JournalInternational Journal of Cancer
DOIs
Publication statusAccepted/In press - Jan 1 2019

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Glioblastoma
Glutamic Acid
Glioma
Therapeutics
Apoptosis
Survival
Brain Edema
Heterografts
Astrocytes
Seizures
Magnetic Resonance Spectroscopy
Stem Cells
Cell Membrane
Injections
Neoplasms

Keywords

  • GLAST/EAAT1
  • glioblastoma
  • glutamate
  • STAT3
  • UCPH-101

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Altered function of the glutamate–aspartate transporter GLAST, a potential therapeutic target in glioblastoma. / 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.

In: International Journal of Cancer, 01.01.2019.

Research output: Contribution to journalArticle

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. / Altered function of the glutamate–aspartate transporter GLAST, a potential therapeutic target in glioblastoma. In: International Journal of Cancer. 2019.
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