Oncotarget

Research Papers:

The peroxisome proliferator activated receptor gamma agonist pioglitazone increases functional expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) in human glioblastoma cells

Jared Ching _, Stephanie Amiridis, Stanley S. Stylli, Andrew R. Bjorksten, Nicole Kountouri, Thomas Zheng, Lucy Paradiso, Rodney B. Luwor, Andrew P. Morokoff, Terence J. O’Brien and Andrew H. Kaye

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Oncotarget. 2015; 6:21301-21314. https://doi.org/10.18632/oncotarget.4019

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Abstract

Jared Ching1,2, Stephanie Amiridis1,2, Stanley S. Stylli1,4, Andrew R. Bjorksten3, Nicole Kountouri1, Thomas Zheng2, Lucy Paradiso1, Rodney B. Luwor1, Andrew P. Morokoff1,4, Terence J. O’Brien2, Andrew H. Kaye1,4

1Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia

2Department of Medicine, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia

3Department of Anaesthesia and Pain Management, The Royal Melbourne Hospital, Victoria, Australia

4Department of Neurosurgery, The Royal Melbourne Hospital, Victoria, Australia

Correspondence to:

Andrew H. Kaye, e-mail: a.kaye@unimelb.edu.au

Keywords: glutamate, pioglitazone, PPAR gamma, glioblastoma multiforme, EAAT2

Received: March 19, 2015     Accepted: May 21, 2015     Published: June 03, 2015

ABSTRACT

Glioma cells release glutamate through expression of system xc-, which exchanges intracellular glutamate for extracellular cysteine. Lack of the excitatory amino acid transporter 2 (EAAT2) expression maintains high extracellular glutamate levels in the glioma microenvironment, causing excitotoxicity to surrounding parenchyma. Not only does this contribute to the survival and proliferation of glioma cells, but is involved in the pathophysiology of tumour-associated epilepsy (TAE). We investigated the role of the peroxisome proliferator activated receptor gamma (PPARγ) agonist pioglitazone in modulating EAAT2 expression in glioma cells. We found that EAAT2 expression was increased in a dose dependent manner in both U87MG and U251MG glioma cells. Extracellular glutamate levels were reduced with the addition of pioglitazone, where statistical significance was reached in both U87MG and U251MG cells at a concentration of ≥ 30 μM pioglitazone (p < 0.05). The PPARγ antagonist GW9662 inhibited the effect of pioglitazone on extracellular glutamate levels, indicating PPARγ dependence. In addition, pioglitazone significantly reduced cell viability of U87MG and U251MG cells at ≥ 30 μM and 100 μM (p < 0.05) respectively. GW9662 also significantly reduced viability of U87MG and U251MG cells with 10 μM and 30 μM (p < 0.05) respectively. The effect on viability was partially dependent on PPARγ activation in U87MG cells but not U251MG cells, whereby PPARγ blockade with GW9662 had a synergistic effect. We conclude that PPARγ agonists may be therapeutically beneficial in the treatment of gliomas and furthermore suggest a novel role for these agents in the treatment of tumour associated seizures through the reduction in extracellular glutamate.


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