Increased Expression of System xc− in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance

Abstract

Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor in adults. Several studies have shown that glioma cells up-regulate the expression of xCT (SLC7A11), the catalytic subunit of system xc−, a transporter involved in cystine import, that modulates glutathione production and glioma growth. However, the role of system xc− in regulating the sensitivity of glioma cells to chemotherapy is currently debated. Inhibiting system xc− with sulfasalazine decreased glioma growth and survival via redox modulation, and use of the chemotherapeutic agent temozolomide together with sulfasalazine had a synergistic effect on cell killing. To better understand the functional consequences of system xc− in glioma, stable SLC7A11 knock-down and over-expressing U251 glioma cells were generated. Modulation of SLC7A11 did not alter cellar proliferation but over-expression did increase anchorage-independent cell growth. Knock-down of SLC7A11 increased basal ROS and decreased glutathione generation resulting in increased cell death under oxidative and genotoxic stress. Over-expression of SLC7A11 resulted in increased resistance to oxidative stress and decreased chemosensitivity to temozolomide. In addition, SLC7A11 over-expression was associated with altered cellular metabolism including increased mitochondrial biogenesis, oxidative phosphorylation and ATP generation. These results suggest that expression of SLC7A11 in the context of glioma contributes to tumorigenesis, tumor progression, and resistance to standard chemotherapy. Implications: SLC7A11, in addition to redox modulation, appears to be associated with increased cellular metabolism and is a mediator of temozolomide resistance in human glioma, thus making system xC− a potential therapeutic target in GBM.

The glutamate/cystine antiporter SLC7A11/xCT enhances cancer cell dependency on glucose by exporting glutamate

“…It will be interesting to further explore the biological impact of SLC7A11-mediated glutamate efflux under other stress conditions. Second, previous studies revealed that, in different cancer cell lines, SLC7A11 overexpression generally confers resistance to cell death induced by various stress conditions, such as oxidative stress, genotoxic stress, and proteasome inhibition, whereas SLC7A11 deficiency increases sensitivity to stress-induced cell death (22,27,28). It is generally accepted that SLC7A11medated cystine uptake and glutathione biosynthesis underlie its pro-survival function under these stress conditions.…”

Cystine uptake through the cystine/glutamate antiporter xCT triggers glioblastoma cell death under glucose deprivation

“…Cancer cells also exhibit altered amino acid uptake and utilization, and therefore they often express high levels of cell surface amino acid transporters. Among them, xCT (SLC7A11), the light chain of the cystine/glutamate antiporter system x c Ϫ , is up-regulated in brains of patients with glioblastoma and in glioblastoma cell lines, and its expression correlates with tumor invasion and poor survival (11)(12)(13)(14)(15)(16)(17). The system x c…”

Seizures in patients with cancer

“…In high‐grade gliomas, glutamate also plays an important role in epileptogenicity. SLC7A11/xCT, the catalytic subunit of system (SXC) and a membrane antiporter that couples the efflux of glutamate with the influx of cystine, is upregulated in >50% of high‐grade gliomas . The upregulation of xCT leads to increased glutamate efflux, promoting excitotoxicity, seizures, and neuronal death .…”

“…SLC7A11/xCT, the catalytic subunit of system (SXC) and a membrane antiporter that couples the efflux of glutamate with the influx of cystine, is upregulated in >50% of high‐grade gliomas . The upregulation of xCT leads to increased glutamate efflux, promoting excitotoxicity, seizures, and neuronal death . Newly described glutamatergic synapses between neurons and tumor cells are also thought to mediate signaling associated with tumor growth .…”

“…36,37 The upregulation of xCT leads to increased glutamate efflux, promoting excitotoxicity, seizures, and neuronal death. 36,37 Newly described glutamatergic synapses between neurons and tumor cells are also thought to mediate signaling associated with tumor growth. [38][39][40] In gliomas, neuronal activity promotes tumor growth and invasion through glutamate activation of AMPA receptors in neuron-glioma synapses, and this growth appears to be abated by the AMPA receptor antagonist perampanel.…”