Dataset Information

Distribution of cystine/glutamate exchange transporter, system x(c)-, in the mouse brain.

ABSTRACT: Mammalian cells express a transport system known as system x(c)-, which is an exchange agency specific for anionic forms of cystine and glutamate. System x(c)- activity is important to maintain both intracellular glutathione levels and the redox balance between cystine and cysteine in the extracellular milieu. We have shown that the cloned cDNAs encoding the transporter for system x(c)- consist of two components, xCT and the heavy chain of 4F2 antigen. In the present study, we have investigated the mRNA distribution for these components in the mouse brain by in situ hybridization. The xCT mRNA was expressed in the area postrema, subfornical organ, habenular nucleus, hypothalamic area, and ependymal cells of the lateral wall of the third ventricle in the adult mouse brain. A strong signal was also detected in the meninges in both adult and fetal mouse brains. The mRNA expression of the heavy chain of 4F2 antigen was detected in a more broad area, including all of the regions in which xCT mRNA was detected. These data are compatible with our biochemical evidence that xCT functions in combination with the heavy chain of 4F2 antigen to elicit system x(c)- activity. The expression of system x(c)- in meninges and some circumventricular organs may suggest that this transporter contributes to the maintenance of the redox state (i.e., cysteine/cystine ratio) in the CSF.

SUBMITTER: Sato H

PROVIDER: S-EPMC6758101 | biostudies-literature | 2002 Sep

REPOSITORIES: biostudies-literature

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Distribution of cystine/glutamate exchange transporter, system x(c)-, in the mouse brain.

Sato Hideyo H Tamba Michiko M Okuno Suzuka S Sato Kanako K Keino-Masu Kazuko K Masu Masayuki M Bannai Shiro S

The Journal of neuroscience : the official journal of the Society for Neuroscience 20020901 18

Mammalian cells express a transport system known as system x(c)-, which is an exchange agency specific for anionic forms of cystine and glutamate. System x(c)- activity is important to maintain both intracellular glutathione levels and the redox balance between cystine and cysteine in the extracellular milieu. We have shown that the cloned cDNAs encoding the transporter for system x(c)- consist of two components, xCT and the heavy chain of 4F2 antigen. In the present study, we have investigated ...[more]

PMID: 12223556

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Project description:BackgroundThe upregulation of antioxidant mechanisms is a common occurrence in cancer cells, as they strive to maintain balanced redox state and prevent oxidative damage. This includes the upregulation of the cystine/glutamate antiporter xCT, which plays a crucial role in protecting cancer cells from oxidative stress. Consequently, targeting xCT has become an attractive strategy for cancer treatment. However, xCT is also expressed by several types of immune cells where it has a role in proliferation and effector functions. In light of these observations, a comprehensive understanding of the specific role of xCT in the initiation and progression of cancer, as well as its potential impact on the immune system within the tumor microenvironment and the anti-tumor response, require further investigation.MethodsWe generated xCTnull BALB/c mice to investigate the role of xCT in the immune system and xCTnull/Erbb2-transgenic BALB-neuT mice to study the role of xCT in a mammary cancer-prone model. We also used mammary cancer cells derived from BALB-neuT/xCTnull mice and xCTKO 4T1 cells to test the contribution of xCT to malignant properties in vitro and in vivo.ResultsxCT depletion in BALB-neuT/xCTnull mice does not alter autochthonous tumor initiation, but tumor cells isolated from these mice display proliferation and redox balance defects in vitro. Although xCT disruption sensitizes 4T1 cells to oxidative stress, it does not prevent transplantable tumor growth, but reduces cell migration in vitro and lung metastasis in vivo. This is accompanied by an altered immune cell recruitment in the pre-metastatic niche. Finally, systemic depletion of xCT in host mice does not affect transplantable tumor growth and metastasis nor impair the proper mounting of both humoral and cellular immune responses in vivo.ConclusionsxCT is dispensable for proper immune system function, thus supporting the safety of xCT targeting in oncology. Nevertheless, xCT is involved in several processes required for the metastatic seeding of mammary cancer cells, thus broadening the scope of xCT-targeting approaches.

Project description:The cystine-glutamate antiporter (system xc-) is a Na+-independent amino acid transporter that exchanges extracellular cystine for intracellular glutamate. It is thought to play a critical role in cellular redox processes through regulation of intracellular glutathione synthesis via cystine uptake. In gliomas, system xc- expression is universally up-regulated while that of glutamate transporters down-regulated, leading to a progressive accumulation of extracellular glutamate and excitotoxic cell death of the surrounding non-tumorous tissue. Additionally, up-regulation of system xc- in activated microglia has been implicated in the pathogenesis of several neurodegenerative disorders mediated by excess glutamate. Consequently, system xc- is a new drug target for brain cancer and neuroinflammatory diseases associated with excess extracellular glutamate. Unfortunately no potent and selective small molecule system xc- inhibitors exist and to our knowledge, no high throughput screening (HTS) assay has been developed to identify new scaffolds for inhibitor design. To develop such an assay, various neuronal and non-neuronal human cells were evaluated as sources of system xc-. Human glioma cells were chosen based on their high system xc- activity. Using these cells, [14C]-cystine uptake and cystine-induced glutamate release assays were characterized and optimized with respect to cystine and protein concentrations and time of incubation. A pilot screen of the LOPAC/NINDS libraries using glutamate release demonstrated that the logistics of the assay were in place but unfortunately, did not yield meaningful pharmacophores. A larger, HTS campaign using the 384-well cystine-induced glutamate release as primary assay and the 96-well 14C-cystine uptake as confirmatory assay is currently underway. Unexpectedly, we observed that the rate of cystine uptake was significantly faster than the rate of glutamate release in human glioma cells. This was in contrast to the same rates of cystine uptake and glutamate release previously reported in normal human fibroblast cells.

Dataset Information

Distribution of cystine/glutamate exchange transporter, system x(c)-, in the mouse brain.

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Distribution of cystine/glutamate exchange transporter, system x(c)-, in the mouse brain.

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