Blockage of Ca2+-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells

Ishiuchi, Shogo; Tsuzuki, Keisuke; Yoshida, Yukari; Yamada, Nobuaki; Hagimura, Norikazu; Okado, Haruo; Miwa, Akiko; Kurihara, Hideyuki; Nakazato, Yoichi; Tamura, Masahito; Sasaki, Tatsuya; Ozawa, Seiji

doi:10.1038/nm746

Cited by 283 publications

(313 citation statements)

References 31 publications

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“…Moreover, adenoviral-mediated delivery of edited and thus Ca 2 þ impermeable GluR2 into CGNH-89 glioma cells impaired their proliferative activity and increased apoptosis. Conversely, overexpression of the unedited, Ca 2 þ permeable GluR2(Q) subunit augmented CGNH-89 glioma cell proliferation (Ishiuchi et al, 2002). In clear contrast to these studies, it has been recently suggested that glioma cells survive glutamate-rich, excitotoxic environment due to intrinsic glutamate receptor inactivation, which is supported by the finding that GluR subunits are transcriptionally downregulated in glioma specimens (van Vuurden et al, 2009). Owing to this caveat and the apparent importance of glutamate signaling for potential glioma therapy, we analyzed in detail the effects of genetic and pharmaco logical interference with glutamate secretion and cystine incorporation mediated by system X c À as well as glutamate receptor agonism and antagonism on glioma growth in vitro and ex vivo.…”

Section: Introductionmentioning

confidence: 98%

“…Even though the glioma-promoting properties of glutamate release by glioma cells appear to be without doubt, the underlying mechanisms are still poorly understood. Besides neurotoxic effects, some studies assume that extracellular glutamate promotes glioma proliferation in an autocrine or paracrine manner by activation of ionotropic glutamate receptors on gliomas, especially of the (RS)-a-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate (AMPA) subtype (Ishiuchi et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

et al. 2010

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Malignant glioma represents one of the most aggressive and lethal human neoplasias. A hallmark of gliomas is their rapid proliferation and destruction of vital brain tissue, a process in which excessive glutamate release by glioma cells takes center stage. Pharmacologic antagonism with glutamate signaling through ionotropic glutamate receptors attenuates glioma progression in vivo, indicating that glutamate release by glioma cells is a prerequisite for rapid glioma growth. Glutamate has been suggested to promote glioma cell proliferation in an autocrine or paracrine manner, in particular by activation of the (RS)-a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate (AMPA) subtype of glutamate receptors. Here, we dissect the effects of glutamate secretion on glioma progression. Glioma cells release glutamate through the amino-acid antiporter system X c À , a process that is mechanistically linked with cystine incorporation. We show that disrupting glutamate secretion by interfering with the system X c À activity attenuates glioma cell proliferation solely cystine dependently, whereas glutamate itself does not augment glioma cell growth in vitro. Neither AMPA receptor agonism nor antagonism affects glioma growth in vitro. On a molecular level, AMPA insensitivity is concordant with a pronounced transcriptional downregulation of AMPA receptor subunits or overexpression of the fully edited GluR2 subunit, both of which block receptor activity. Strikingly, AMPA receptor inhibition in tumorimplanted brain slices resulted in markedly reduced tumor progression associated with alleviated neuronal cell death, suggesting that the ability of glutamate to promote glioma progression strictly requires the tumor microenvironment. Concerning a potential pharmacotherapy, targeting system X c À activity disrupts two major pathophysiological properties of glioma cells, that is, the induction of excitotoxic neuronal cell death and incorporation of cystine required for rapid proliferation.

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

et al. 2010

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“…In migratory glioma cells, similar Ca 2+ oscillations are reported in response to activation of ACh-R (Bordey et al, 2000), which activate charybdotoxin-sensitive BK K + channels. Moreover, glioma cells express Ca 2+ -permeable AMPA receptors, and Ca 2+ influx through these receptors is required for cell migration (Ishiuchi et al, 2002). Hence, receptormediated activation of Ca 2+ influx into either migratory granule cells or glioma cells appears to be a prerequisite for cell migration: we suspect that this Ca 2+ signal is instructive with regards to cell-volume changes that occur down-stream.…”

Section: Discussionmentioning

confidence: 96%

A role for ion channels in glioma cell invasion

McFerrin¹,

2005

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Many cells, including neuronal and glial progenitor cells, stem cells and microglial cells, have the capacity to move through the extracellular spaces of the developing and mature brain. This is particularly pronounced in astrocyte-derived tumors, gliomas, which diffusely infiltrate the normal brain. Although a significant body of literature exists regarding signals that are involved in the guidance of cells and their processes, little attention has been paid to cell-shape and cell-volume changes of migratory cells. However, extracellular spaces in the brain are very narrow and represent a major obstacle that requires cells to dynamically regulate their volume. Recent studies in glioma cells show that this involves the secretion of Cl − and K + with water. Pharmacological inhibition of Cl − channels impairs their ability to migrate and limits tumor progression in experimental tumor models. One Cl − -channel inhibitor, chlorotoxin, is currently in Phase II clinical trials to treat malignant glioma. This article reviews our current knowledge of cell-volume changes and the role of ion channels during the migration of glioma cells. It also discusses evidence that supports the importance of channel-mediated cell-volume changes in the migration of immature neurons and progenitor cells during development. New unpublished data is presented, which demonstrates that Cl − and K + channels involved in cell shrinkage localize to lipid-raft domains on the invadipodia of glioma cells and that their presence might be regulated by trafficking of these proteins in and out of lipid rafts.

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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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Blockage of Ca2+-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells

Cited by 283 publications

References 31 publications

Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

A role for ion channels in glioma cell invasion

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

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