PMID- 26046374 OWN - NLM STAT- MEDLINE DCOM- 20160610 LR - 20201209 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 6 IP - 25 DP - 2015 Aug 28 TI - 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. PG - 21301-14 AB - 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 (PPARgamma) 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 muM pioglitazone (p < 0.05). The PPARgamma antagonist GW9662 inhibited the effect of pioglitazone on extracellular glutamate levels, indicating PPARgamma dependence. In addition, pioglitazone significantly reduced cell viability of U87MG and U251MG cells at >/= 30 muM and 100 muM (p < 0.05) respectively. GW9662 also significantly reduced viability of U87MG and U251MG cells with 10 muM and 30 muM (p < 0.05) respectively. The effect on viability was partially dependent on PPARgamma activation in U87MG cells but not U251MG cells, whereby PPARgamma blockade with GW9662 had a synergistic effect. We conclude that PPARgamma 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. FAU - Ching, Jared AU - Ching J AD - Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia. AD - Department of Medicine, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia. FAU - Amiridis, Stephanie AU - Amiridis S AD - Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia. AD - Department of Medicine, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia. FAU - Stylli, Stanley S AU - Stylli SS AD - Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia. AD - Department of Neurosurgery, The Royal Melbourne Hospital, Victoria, Australia. FAU - Bjorksten, Andrew R AU - Bjorksten AR AD - Department of Anaesthesia and Pain Management, The Royal Melbourne Hospital, Victoria, Australia. FAU - Kountouri, Nicole AU - Kountouri N AD - Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia. FAU - Zheng, Thomas AU - Zheng T AD - Department of Medicine, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia. FAU - Paradiso, Lucy AU - Paradiso L AD - Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia. FAU - Luwor, Rodney B AU - Luwor RB AD - Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia. FAU - Morokoff, Andrew P AU - Morokoff AP AD - Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia. AD - Department of Neurosurgery, The Royal Melbourne Hospital, Victoria, Australia. FAU - O'Brien, Terence J AU - O'Brien TJ AD - Department of Medicine, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia. FAU - Kaye, Andrew H AU - Kaye AH AD - Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia. AD - Department of Neurosurgery, The Royal Melbourne Hospital, Victoria, Australia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 RN - 0 (2-chloro-5-nitrobenzanilide) RN - 0 (Anilides) RN - 0 (Excitatory Amino Acid Transporter 2) RN - 0 (Glutamate Plasma Membrane Transport Proteins) RN - 0 (PPAR gamma) RN - 0 (SLC1A2 protein, human) RN - 0 (Thiazolidinediones) RN - 3KX376GY7L (Glutamic Acid) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) RN - X4OV71U42S (Pioglitazone) SB - IM MH - Anilides/chemistry MH - Animals MH - Brain/drug effects MH - Brain Neoplasms/drug therapy/*metabolism MH - Cell Line, Tumor MH - Cell Survival MH - Dose-Response Relationship, Drug MH - Excitatory Amino Acid Transporter 2 MH - Gene Expression Profiling MH - Gene Expression Regulation, Neoplastic MH - Glioblastoma/drug therapy/*metabolism MH - Glutamate Plasma Membrane Transport Proteins/*metabolism MH - Glutamic Acid/chemistry MH - Glycogen Synthase Kinase 3/metabolism MH - Glycogen Synthase Kinase 3 beta MH - Humans MH - Neoplasm Transplantation MH - PPAR gamma/*agonists/metabolism MH - Pioglitazone MH - Rats MH - Rats, Wistar MH - Seizures/prevention & control MH - Thiazolidinediones/*chemistry PMC - PMC4673266 OTO - NOTNLM OT - EAAT2 OT - PPAR gamma OT - glioblastoma multiforme OT - glutamate OT - pioglitazone COIS- CONFLICTS OF INTEREST The authors have no conflicts of interest to disclose. EDAT- 2015/06/06 06:00 MHDA- 2016/06/11 06:00 PMCR- 2015/08/28 CRDT- 2015/06/06 06:00 PHST- 2015/03/19 00:00 [received] PHST- 2015/05/21 00:00 [accepted] PHST- 2015/06/06 06:00 [entrez] PHST- 2015/06/06 06:00 [pubmed] PHST- 2016/06/11 06:00 [medline] PHST- 2015/08/28 00:00 [pmc-release] AID - 4019 [pii] AID - 10.18632/oncotarget.4019 [doi] PST - ppublish SO - Oncotarget. 2015 Aug 28;6(25):21301-14. doi: 10.18632/oncotarget.4019.