Small interfering RNA–mediated xCT silencing in gliomas inhibits neurodegeneration and alleviates brain edema

Savaskan, Nicolai Ε.; Heckel, Alexandra; Hahnen, Eric; Engelhorn, Tobias; Doerfler, Arnd; Ganslandt, Oliver; Nimsky, Christopher; Buchfelder, Michael; Eyüpoglu, Ilker Y.

doi:10.1038/nm1772

Cited by 175 publications

(214 citation statements)

References 13 publications

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“…In line with these findings, enhancing EAAT2 expression in grafted C6 rat glioma cells reduced tumor size and elevated the life span of tumor-bearing animals (Vanhoutte et al, 2009). Moreover, inhibition of glutamate release via system X c À , consisting of xCT (SLC7A11) and CD98 (SLC3A2, 4F2HC), profoundly decelerates the glioma phenotype in vivo (Chung et al, 2005;Lyons et al, 2007;Savaskan et al, 2008) and in addition mitigates tumor-induced brain swelling (Savaskan et al, 2008). Even though the glioma-promoting properties of glutamate release by glioma cells appear to be without doubt, the underlying mechanisms are still poorly understood.…”

Section: Introductionmentioning

confidence: 67%

“…Subsequently, we analyzed the effects of (S)-4CPG, a competitive small molecule inhibitor targeting system X c À activity and thus glutamate release Patel et al, 2004;Savaskan et al, 2008). As suggested, the ability of (S)-4CPG to reduce F98 glioma cell growth (using medium containing 10% FCS) is essentially dependent on the concentrations of extracellular cystine (Figure 3a).…”

Section: Resultsmentioning

confidence: 92%

“…Despite multimodal therapy regimens including neurosurgical resection, radiotherapy and cytotoxic chemotherapy, the prognosis of glioma patients remains poor, that is, o3% of patients survive more than 5 years (Ohgaki and Kleihues, 2005). Rapid proliferation, diffuse brain invasion as well as tumor-induced brain edema and neurodegeneration are pathological hallmarks of these tumors and are likely to determine unfavorable prognosis (Savaskan et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Numerous studies showed that glioma cells secrete high levels of the neurotransmitter glutamate, resulting in neuronal cell death Behrens et al, 2000;Savaskan et al, 2008;Marcus et al, 2010) and brain edema (Savaskan et al, 2008) through excitatory activation of neuronal glutamate receptors. Glutamate receptor antagonists block neuronal degeneration in the tumor vicinity and lessen glioma growth in vivo, suggesting that neurodegeneration is a prerequisite for rapid glioma progression (Takano et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Excessive glutamate release by glioma cells has been linked to decreased activities of glial glutamate transporters such as EAAT1 (GLAST, SLC1A3) and EAAT2 (GLT-1, SLC1A2), resulting in decreased glutamate incorporation and consequently reduced extracellular glutamate clearance. In addition, the antiporter system X c À , mediating glutamate release in exchange for cystine, is abundantly expressed in glioblastoma specimens and cell lines Lyons et al, 2007;Savaskan et al, 2008Savaskan et al, , 2009. As a result, reduced EAAT1 and EAAT2 expression and concurrently abundant system X c À activity result in a net balance shifted toward glutamate release, thus promoting glioma progression.…”

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: 67%

Section: Resultsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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From bedside to bench: New insights in epilepsy‐associated tumors based on recent classification updates and animal models on brain tumor networks

Cases‐Cunillera,

Friker,

Müller

et al. 2024

Molecular Oncology

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Low‐grade neuroepithelial tumors (LGNTs), particularly those with glioneuronal histology, are highly associated with pharmacoresistant epilepsy. Increasing research focused on these neoplastic lesions did not translate into drug discovery; and anticonvulsant or antitumor therapies are not available yet. During the last years, animal modeling has improved, thereby leading to the possibility of generating brain tumors in mice mimicking crucial genetic, molecular and immunohistological features. Among them, intraventricular in utero electroporation (IUE) has been proven to be a valuable tool for the generation of animal models for LGNTs allowing endogenous tumor growth within the mouse brain parenchyma. Epileptogenicity is mostly determined by the slow‐growing patterns of these tumors, thus mirroring intrinsic interactions between tumor cells and surrounding neurons is crucial to investigate the mechanisms underlying convulsive activity. In this review, we provide an updated classification of the human LGNT and summarize the most recent data from human and animal models, with a focus on the crosstalk between brain tumors and neuronal function.

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MiR‐375/SLC7A11 axis regulates oral squamous cell carcinoma proliferation and invasion

et al. 2017

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We aimed to detect the functions of miR‐375/SLC7A11 axis on oral squamous cell carcinoma (OSCC) cell proliferation and invasion. Expression levels of miR‐375 and SLC7A11 in OSCC tissues and cells were measured with RT‐qPCR and western blot. Targeting site was predicted by TargetScan and confirmed by dual luciferase reporting assay. By way of manipulating the expression level of miR‐375 and SLC7A11 in CAL‐27 and Tca8113 cell lines, the cell biological abilities were evaluated. MTT, colony formation, Transwell, wound healing assays and flow cytometry were used to detect OSCC cell viability, proliferation, invasion, migration and apoptosis, respectively. MiR‐375 was significantly downregulated in OSCC tissues and cells compared to adjacent tissue and normal oral cell line respectively while SLC7A11 was upregulated. Targeting relationship was verified by luciferase reporting assay, and miR‐375 could effectively suppress SLC7A11 level in OSCC cells. Replenishing of miR‐375 significantly repressed OSCC cell viability, proliferation, invasion and migration and induced cell apoptosis and G1/G0 arrest. Overexpression of SLC7A11 recovered those biological abilities in miR‐375 upregulated cells. Collective data suggested that miR‐375 served as a tumor suppressor via regulating SLC7A11. Replenishing of miR‐375 or knockout of SLC7A11 could be therapeutically exploited.

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Small interfering RNA–mediated xCT silencing in gliomas inhibits neurodegeneration and alleviates brain edema

Cited by 175 publications

References 13 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

From bedside to bench: New insights in epilepsy‐associated tumors based on recent classification updates and animal models on brain tumor networks

MiR‐375/SLC7A11 axis regulates oral squamous cell carcinoma proliferation and invasion

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