Inhibition of xCT Suppresses Melanoma progress
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE166566 | GEO | 2021/02/11
REPOSITORIES: GEO
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Project description:Kaposiâs sarcoma-associated herpesvirus (KSHV) is the etiological agent of primary effusion lymphoma (PEL), a rapidly progressing malignancy mostly arising in HIV-infected patients. Even under conventional chemotherapy, PEL continues to portend nearly 100% mortality within several months, which urgently requires novel therapeutic strategies. We have previously demonstrated that targeting xCT, an amino acid transporter for cystine/glutamate exchange, induces significant PEL cell apoptosis through regulation of multiple host and viral factors. More importantly, one of xCT selective inhibitors, Sulfasalazine (SASP), effectively prevents PEL tumor progression in an immune-deficient xenograft model. In the current study, we use Illumina microarray to explore the genomic gene profile altered by SASP treatment within 3 KSHV+ PEL cell-lines, and discover that many genes involved in oxidative stress/antioxidant defense system, apoptosis/anti-apoptosis/cell death, and cellular response to unfolded proteins/topologically incorrect proteins are potentially regulated by xCT. We further functionally validate 2 downstream candidates, OSGIN1 (Oxidative stress-induced growth inhibitor 1) and XRCC5 (X-ray repair cross-complementing protein 5), their relationship with PEL cell survival/proliferation and chemoresistance, respectively. Together, our data indicate that targeting these xCT-regulated novel downstream genes may help devise promising therapeutic strategies against PEL and/or other AIDS-related lymphoma. 3 KSHV PEL cell lines were treated with xCT selective inhibitor Sulfasalazine (SASP) and the gene expression signature was compared to that of untreated cells
2015-11-23 | E-GEOD-65418 | biostudies-arrayexpress
Project description:Inhibition of xCT Suppresses Melanoma progress
| PRJNA701281 | ENA
Project description:Mutations in cancer reprogram amino acid metabolism to drive tumor growth, but the molecular mechanisms are not well understood. Using an unbiased proteomic screen, we identified mTORC2 as a critical regulator of amino acid metabolism in cancer via phosphorylation of the cystine-glutamate antiporter xCT. mTORC2 phosphorylates serine 26 at the cytosolic N-terminus of xCT, inhibiting its activity. Genetic inhibition of mTORC2, or pharmacologic mTOR kinase inhibition, promotes glutamate secretion, cystine uptake and incorporation into glutathione linking growth factor receptor signaling with amino acid uptake and utilization. These results identify an unanticipated mechanism of amino acid metabolic reprogramming in cancer, enabling tumor cells to adapt to changing environmental conditions.
2017-06-28 | PXD006461 | Pride
Project description:Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of primary effusion lymphoma (PEL), a rapidly progressing malignancy mostly arising in HIV-infected patients. Even under conventional chemotherapy, PEL continues to portend nearly 100% mortality within several months, which urgently requires novel therapeutic strategies. We have previously demonstrated that targeting xCT, an amino acid transporter for cystine/glutamate exchange, induces significant PEL cell apoptosis through regulation of multiple host and viral factors. More importantly, one of xCT selective inhibitors, Sulfasalazine (SASP), effectively prevents PEL tumor progression in an immune-deficient xenograft model. In the current study, we use Illumina microarray to explore the genomic gene profile altered by SASP treatment within 3 KSHV+ PEL cell-lines, and discover that many genes involved in oxidative stress/antioxidant defense system, apoptosis/anti-apoptosis/cell death, and cellular response to unfolded proteins/topologically incorrect proteins are potentially regulated by xCT. We further functionally validate 2 downstream candidates, OSGIN1 (Oxidative stress-induced growth inhibitor 1) and XRCC5 (X-ray repair cross-complementing protein 5), their relationship with PEL cell survival/proliferation and chemoresistance, respectively. Together, our data indicate that targeting these xCT-regulated novel downstream genes may help devise promising therapeutic strategies against PEL and/or other AIDS-related lymphoma.
2015-11-23 | GSE65418 | GEO
Project description:The major antioxidant glutathione (GSH) protects cancer cells from oxidative damage leading to ferroptosis, an iron-dependent cell death. Therapy-resistant cancer cells often manifest high expression of the cystine-glutamate antiporter subunit xCT which enhances cystine uptake leading to GSH synthesis and thereby survive oxidative damage and ferroptosis. The use of GSH-depleting agents including xCT inhibitors might thus be expected to enhance the efficacy of cancer therapy. On the other hand, the efficacy of xCT-targeted therapy depends on the cellular metabolism affecting antioxidant system in cancer cells and metabolic reprograming might reduce the efficacy of cancer therapy using xCT inhibitors. Recently, to overcome the resistance to xCT-targeted therapy, we performed a library screening and identified an oral anesthetics dyclonine (DYC) as a sensitizing drug for xCT inhibitor sulfasalazine (SSZ). However, DYC is a local anesthetic and might not suitable for the systemic administration combined with SSZ in a clinical setting. In this study, we identified a vasodilator oxyfedrine (OXY) which is clinically used in systemic administration also acts as a sensitizing drug to GSH-depleting agents in multiple type of cancer cells. OXY and DYC share the motif required for the covalent inhibition of aldehyde dehydrogenases (ALDHs), and combined treatment with OXY and SSZ induced the accumulation of cytotoxic aldehyde 4-hydroxynonenal (4-HNE) and induce cell death in SSZ-resistant cancer cells. Furthermore, we found that OXY sensitizes cancer cells to radiation therapy which decreases intracellular GSH content. Our findings establish a rationale for repurposing of OXY as a sensitizing drug for xCT-targeted cancer therapy.
2019-09-25 | GSE137952 | GEO
Project description:We demonstrate that stress differentially regulates glutamate homeostasis in the dorsal and ventral hippocampus and established a previously unknown role for the glial marker xCT in the homeostatic regulation of the ventral dentate gyrus (vDG) in stress resilience and antidepressant responses. We provide RNAseq roadmap for the stress-sensitive vDG and show that the transcription factor REST binds to xCT promoter in co-occupancy with the epigenetic marker H3K27acet, to negatively regulate xCT expression. Reduced xCT was also observed in a genetic mouse model of inherent susceptibility to depression. Pharmacologically modulating histone acetylation with next-generation therapeutics, such as acetyl-N-cysteine (NAC) or acetyl-L-carnitine (LAC), rapidly increased xCT reduction and activated a network that included mGlu2 receptors to prime an enhanced glutamate homeostasis that promoted stress resilience and antidepressant-like responses. Moreover, pharmacological xCT blockage counteracted NAC prophylactic effects. Anatomical (vDG) and cell-type specific (GFAP+) virus-overexpression mimicked the effects of pharmacological treatments in increasing stress resilience. These findings establish xCT as critical regulator of the glutamate system in a network with mGlu2 receptors. These studies also point to a role of histone acetylation as mediator of stress resilience.
2017-10-11 | GSE103435 | GEO
Project description:Objectives: Epileptogenesis in human glioma is linked to increased glutamate signaling that is primarily facilitated by xCT, suggesting it as a pharmacological target for anti-seizure medication (ASM). Here, we investigated the expression of xCT in glioma-associated epilepsy and investigated the impact of both tumor-associated epilepsy and xCT expression levels on the glioma proteome. Methods: We quantified the expression of xCT and its subunit SLC3A2 by immunoblot in snap-frozen tissue of tumor treatment-naïve IDH-mutant and IDH-wildtype gliomas (n=93) in cases with and without epilepsy (controls)and control cases and compared it to the levels of excitatory amino acid transporter 2 (EAAT2) and the solute carrier family 1 member 4 (SLC1A4). Additionally, we performed whole cell proteomics in IDH-wildtype glioblastoma (GB) from 16 patients with or without epilepsy, and with low or high xCT protein expression. Results: In cases with epilepsy, we observed a trend towards higher expression of xCT and found that EAAT2 and SLC1A4 were significantly higher expressed. Quantitative proteomics of IDH-wildtype GB with epilepsy versus control identified 214 proteins to be significantly regulated. Upregulated proteins showed enrichment for Gene Ontology (GO) terms involving neurotransmitter and amino acid turnover as well as lipid metabolism. Within the epilepsy group, we found a distinction between xCT low- and high-expressing tumors. Of the 231 proteins that were increased in xCT high-expressing tumors, 35 overlapped with proteins upregulated in the epilepsy cohort. These proteins again clustered for GO-BP terms involving neurotransmitter and amino acid metabolism. In addition, xCT high-expressing tumors showed upregulation of proteins that clustered for myelination and regulation of synaptic plasticity. In the survival analysis, epilepsy and high xCT expression did not influence the outcome of patients with either IDH-mutant or IDH-wildtype tumors. Significance: Our results show differences in the proteome of gliomas with and without epilepsyseizures and illustrate that xCT expression levels impact the protein network of these tumors. Our study provides insights into the biological network of these tumors that may be relevant for the development of targeted ASM.
2026-03-21 | PXD062733 | Pride
Project description:To identify the genes involving in the resistance to xCT inhibitors, we established the sulfasalazine-resistant clone of an oral squamous cell carcinoma OSC19 cell line, and the resulting sulfasalazine-resistant cells and its parental cells were subjected to cDNA microarray analysis.
2018-05-01 | GSE113860 | GEO
Project description:Acinar cell dedifferentiation is one of the most notable features of acute and chronic pancreatitis. It can also be the initial step that facilitates pancreatic cancer development. In the present study, we further decipher the precise mechanism and regulation using murine experimental models. Our RNAseq analysis indicates that, early acinar cell dedifferentiation is accompanied by multiple pathways related to cell survival that are highly enriched, and where SLC7A11 (xCT) is transiently upregulated. xCT is the specific subunit of the cystine/glutamate antiporter system xC-. Acinar cells with depleted or reduced xCT function show an increase in ferroptosis relating to lipid peroxidation. Lower glutathione levels and more lipid ROS accumulation could be rescued by the antioxidant N-acetylcysteine or the ferroptosis inhibitor Ferrostatin-1. In caerulein-induced acute pancreatitis in mice, xCT also prevents lipid peroxidation in acinar cells. In conclusion, during stress, acinar cell fate seems to be poised for avoiding several forms of cell death. xCT specifically prevents acinar cell ferroptosis by fueling the glutathione pool and maintaining ROS balance. The data suggest that xCT offers a druggable tipping point to steer the acinar cell fate in stress conditions.
2023-08-07 | GSE240106 | GEO
Project description:XCT was originally identified due to the short circadian period observed in plants mutant for this gene. Proteins with homology to XCT are found across eukaryotes, but their molecular function is unknown. We have recently demonstrated that in Schizosaccharomyces pombe, the XCT ortholog Xap5 is a chromatin-associated protein that acts in a similar manner as the histone variant H2A.Z to suppress aberrant gene expression. Here, we demonstrate that although XCT and H2A.Z act in similar pathways to control plant development, XCT's role in the circadian clock is independent of H2A.Z.
2019-05-01 | GSE67813 | GEO