Ca<sup>2+</sup>-Permeable AMPA Receptors Regulate Growth of Human Glioblastoma via Akt Activation

Ishiuchi, Shogo; Yoshida, Yukari; Sugawara, Kenichi; Aihara, Masanori; Ohtani, Toshiyuki; Watanabe, Takashi; Saito, Nobuhito; Tsuzuki, Keisuke; Okado, Haruo; Miwa, Akiko; Nakazato, Yoichi; Ozawa, Seiji

doi:10.1523/jneurosci.2180-07.2007

Cited by 177 publications

(161 citation statements)

References 64 publications

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“…[28][29][30] Our data disclose a new function of glutamate in regulating the biology of GSCs. The amount of glutamate released from GSCs in culture (extracellular concentrations ¼ 4-10 mM) was sufficient to activate mGlu3 receptors, which were expressed and functional in all our GSC clones (EC 50 values for glutamate at mGlu3 receptors are reported in Schoepp et al 31. ).…”

Section: Discussionmentioning

confidence: 73%

Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

et al. 2012

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Drug treatment of malignant gliomas is limited by the intrinsic resistance of glioma stem cells (GSCs) to chemotherapy. GSCs isolated from human glioblastoma multiforme (GBM) expressed metabotropic glutamate receptors (mGlu3 receptors). The DNAalkylating agent, temozolomide, killed GSCs only if mGlu3 receptors were knocked down or pharmacologically inhibited. In contrast, mGlu3 receptor blockade did not affect the action of paclitaxel, etoposide, cis-platinum, and irinotecan. mGlu3 receptor blockade enabled temozolomide toxicity by inhibiting a phosphatidylinositol-3-kinase/nuclear factor-jB pathway that supports the expression of O 6 -methylguanine-DNA methyltransferase (MGMT), an enzyme that confers resistance against DNAalkylating agents. In mice implanted with GSCs into the brain, temozolomide combined with mGlu3 receptor blockade substantially reduced tumor growth. Finally, 87 patients with GBM undergoing surgery followed by adjuvant chemotherapy with temozolomide survived for longer time if tumor cells expressed low levels of mGlu3 receptors. In addition, the methylation state of the MGMT gene promoter in tumor extracts influenced survival only in those patients with low expression of mGlu3 receptors in the tumor. These data encourage the use of mGlu3 receptor antagonists as add-on drugs in the treatment of GBM, and suggest that the transcript of mGlu3 receptors should be measured in tumor specimens for a correct prediction of patients' survival in response to temozolomide treatment.

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Section: Discussionmentioning

confidence: 73%

Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

et al. 2012

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“…73 The authors recently demonstrated that higher Ca 2+ permeability influences migration by activating the Akt pathway. 74 Moreover, several editing targets with a role in cell proliferation have been identified. ADAR activity could potentially modify their function.…”

Section: Regulation Of Adar Activitymentioning

confidence: 99%

Proteome diversification by adenosine to inosine RNA-editing

Pullirsch

Jantsch²

2010

RNA Biology

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“…Accordingly, the therapeutic strategies that have been proposed to counteract the Glu-supporting effects on glioma invasiveness which are based on the use of Glu release inhibitors and Glu receptor antagonists [11, 13, 14] are precisely the same as those proposed for the treatment of acute neurodegenerative disorders involving excess Glu in brain such as stroke or head trauma.…”

Section: Introductionmentioning

confidence: 99%

Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas

et al. 2012

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SummaryL-Glutamate (Glu) plays a crucial role in the growth of malignant gliomas. We have established the feasibility of accelerating a naturally occurring brain to-blood Glu efflux by decreasing blood Glu levels with intravenous oxaloacetate, the respective Glu co-substrate of the blood resident enzyme humane glutamate–oxaloacetate transaminase (hGOT). We wished to demonstrate that blood Glu scavenging provides neuroprotection in the case of glioma. We now describe the neuroprotective effects of blood Glu scavenging in a fatal condition such as brain-implanted C6 glioma in rats and brain-implanted human U87 MG glioma in nude mice. Rat (C-6) or human (U87) glioma cells were grafted stereotactically in the brain of rats or mice. After development of tumors, the animals were drinking oxaloacetate with or without injections of hGOT. In addition, mice were treated with combination treatment, which included drinking oxaloacetate with intracutaneous injections of hGOT and intraperitoneal injection of Temozolomide. Animals drinking oxaloacetate with or without injections of hGOT displayed a smaller tumor volume, reduced invasiveness and prolonged survival than control animals drinking saline. These effects were significantly enhanced by Temozolomide in mice, which increased survival by 237%. This is the first demonstration of blood Glu scavenging in brain cancer, and because of its safety, is likely to be of clinical significance for the future treatment of human gliomas. As we demonstrated, the blood glutamate scavenging treatment in combination with TMZ could be a good candidate or as an alternative treatment to the patients that do not respond to TMZ.

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Ca²⁺-Permeable AMPA Receptors Regulate Growth of Human Glioblastoma via Akt Activation

Cited by 177 publications

References 64 publications

Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

Proteome diversification by adenosine to inosine RNA-editing

Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas

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Ca2+-Permeable AMPA Receptors Regulate Growth of Human Glioblastoma via Akt Activation

Cited by 177 publications

References 64 publications

Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

Proteome diversification by adenosine to inosine RNA-editing

Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas

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Product

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Ca²⁺-Permeable AMPA Receptors Regulate Growth of Human Glioblastoma via Akt Activation