Disruption of Redox Balance Enhances the Effects of BRAF-inhibitors in Melanoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Human Homo Sapiens
TISSUE(S): Tumor Cells
DISEASE(S): Cancer
SUBMITTER: 
Simona Codreanu
PROVIDER: ST001339 | MetabolomicsWorkbench | Tue Mar 31 00:00:00 BST 2020
REPOSITORIES: MetabolomicsWorkbench
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| mwtab | Other |
Items per page: 5 1 - 1 of 1 |
Similar Datasets
Project description:Cancer development and progression is intimately related with post-translational protein modifications, e.g., highly reactive thiol moiety of cysteines enables structural rearrangements resulting in redox biological switches. In this context, redox proteomics emerge as a fundamental tool to identify and quantify redox-sensitive proteins and to understand redox mechanisms behind thiol modifications. Given the great variability in redox proteomics protocols, problems including decreased resolution of peptides and low protein amounts even after the enrichment steps may occur. Considering the biological importance of thiol’s oxidation in melanoma, we adapted the biotin-switch assay technique for melanoma cells in order to overcome limitations of the traditional method.
2024-02-28 | PXD049252 | Pride
Project description:The recent incorporation of molecular features into the diagnosis of Glioblastoma Multiforme patients has led to an improved categorisation into different tumour subtypes with different prognosis and disease management. In this work, we have exploited the benefits of genome-wide multiomic approaches to identify potential molecular vulnerabilities existing on GBM patients. We used the Illumina MethylationEPIC Beadchip platform to describe the genome-wide 5mC and 5hmC DNA methylation landscape of a total of 9 patient-derived Glioblastoma Multiforme Cell lines obtained from the human glioblastoma cell culture resource (HGCC) and 4 brain samples obtained from non-tumoral controls
2023-06-01 | E-MTAB-12473 | biostudies-arrayexpress
Project description:Melanoma is the deadliest of skin cancers and has a high tendency to metastasize to distant organs. Calcium and metabolic signals contribute to melanoma invasiveness; however, the underlying molecular details are elusive. The mitochondrial calcium uniporter (MCU) complex is a major route for calcium into the mitochondrial matrix but if and how MCU affects melanoma pathobiology is not understood. Here, we show that MCUA expression correlates with melanoma patient survival, similarly as in kidney, cervical and other cancers, while in pancreatic, breast and liver cancer, this correlation is inverse. Knockdown (KD) of MCUA suppressed melanoma cell growth but promoted migration and invasion in 2D and 3D cultures. In melanoma xenografts, MCUA_KD reduced tumor volumes but promoted lung metastases. Proteomic analyses and protein microarrays identified pathways that link MCUA abundance and melanoma cell phenotype and suggested a major role for metabolic and redox regulation. Accordingly, antioxidants enhanced melanoma cell migration, while pro-oxidants diminished the MCUA_KD-induced invasive phenotype. Furthermore, MCUA_KD amplified the resistance of melanoma cells to immunotherapies and ferroptosis. Col¬lectively, we demonstrate that MCUA controls melanoma aggressive behavior and therapeutic sen¬sitivity. Manipulations of mitochondrial calcium and redox homeostasis, in combination with cur¬rent therapies, should be considered in treating advanced melanoma.
2022-10-30 | PXD029132 | Pride
Project description:Thiol-dependent redox regulation is essential for the rapid adaptation of chloroplast metabolism to unpredictable changes of light intensity. The disulfide reductase activity of thioredoxins (Trxs), which relies on photo-reduced ferredoxin (Fdx) and a Fdx-dependent Trx reductase (FTR), constitutes the Fdx-FTR-Trxs system, which links chloroplast redox regulation to light. In addition, chloroplasts harbor an NADPH-dependent Trx reductase (NTR) with a joint Trx domain, NTRC. The activity of these two redox systems is integrated by the balance of the hydrogen peroxide scavenging enzyme 2-Cys peroxiredoxin (2-Cys Prx), which thus plays a key role in maintaining the reducing capacity of chloroplast Trxs in response to light intensity. Based on the severe phenotype of mutant lines lacking NTRC, it is clear that this enzyme plays an essential role in chloroplast redox homeostasis. However, whether the function of NTRC depends on its capacity of reduce 2-Cys Prxs or has additional targets remains unknown. Here, we have addressed this issue by a comparative analysis of the triple mutant of Arabidopsis thaliana, ntrc-2cpab, simultaneously lacking 2-Cys Prxs and NTRC, and the double mutant 2cpab lacking 2-Cys Prxs. The phenotype of the ntrc-2cpab mutant is indistinguishable of the 2cpab mutant, as shown by growth rate, photosynthesis performance, light-dependent redox regulation of enzyme activity and comparative transcriptomics based RNA-Seq. Based on these results, we propose that the function of NTRC in chloroplast redox homeostasis is exerted by the regulation of the redox balance of 2-Cys Prxs rather than by the direct reduction of additional targets.
2021-09-09 | GSE147793 | GEO
Project description:Nearly 30% of all malignant melanomas harbor somatic mutations in NRAS. However, there are currently no effective targeted therapies for this tumor type. The bromodomain and extra terminal domain (BET) family of proteins are transcriptional regulators that serve as scaffolds to facilitate gene transcription by binding to acetylated lysine residues in the N-terminal tail of histones. BET/BRD proteins have emerged as therapeutic targets in a broad range of tumors. We found that BET proteins are overexpressed in NRAS mutant melanoma, and that high levels of BET family member BRD4 are associated with poor patient survival, suggesting that BRD4 plays a key role in melanoma. Consequently, we hypothesized that these epigenetic regulators constitute potential vulnerabilities that can be exploited for melanoma treatment. We found that genetic or pharmacological inhibition of BET/BRD proteins decreases viability and inhibits proliferation of NRAS mutant melanoma cells, as well as BRAF/MEK-inhibitor resistant melanoma cells harboring concurrent BRAF/NRAS mutations. However, BET inhibitors when used as single agents were either cytostatic (in vitro) or ineffective (in vivo). We therefore evaluated combinations that could maximize the efficacy of BET inhibitors in NRAS mutant melanoma. Here we report that co-targeting BET and MEK synergistically restrained tumor growth and significantly prolonged the survival of NRAS-mutant tumor bearing mice. RNA-sequencing and RPPA analysis revealed that co-treatment with BETi/MEKi synergistically downregulated cell cycle regulators and activated caspase-7. This study demonstrates that combined BET and MEK inhibition elicits robust synergistic therapeutic effects and supports the clinical utility of this combination therapy for NRAS mutant melanoma patients.
2018-02-20 | GSE95153 | GEO
Project description:Clostridium thermocellum is a promising CBP candidate organism capable of directly converting lignocellulosic biomass to ethanol. Low yields, productivities and growth inhibition prevent industrial deployment of this organism for commodity fuel production. Symptoms of potential redox imbalance such as incomplete substrate utilization, and fermentation products characteristic of overflow metabolism, have been observed during growth. This perceived redox imbalance may be in part responsible for the mentioned bioproductivity limitations. Toward better understanding the redox metabolism of C. thermocellum, we analyzed gene expression, using microarrays, during addition of two stress chemicals (methyl viologen and hydrogen peroxide) which we observed to change fermentation redox potential.
2015-07-29 | GSE71465 | GEO
Project description:In this study, we used GC-MS analysis in combination with flux analysis and the Affymetrix ATH1 GeneChip to survey the metabolome and transcriptome of Arabidopsis leaves in response to manipulation of the thiol-disulfide status. Feeding low concentrations of the sulfhydryl reagent dithiothreitol (DTT) for one hour at the end of the dark period led to post-translational redox-activation of ADP-glucose pyrophosphorylase and major alterations in leaf carbon partitioning, including an increased flux into major respiratory pathways, starch- cell-wall-, and amino-acid synthesis and a reduced flux to sucrose. This was accompanied by a decrease in the levels of hexose-phosphates, while metabolites in the second half of the TCA cycle and various amino acids increased, indicating a stimulation of anaplerotic fluxes reliant on α-ketoglutarate. There was also an increase in shikimate as a precursor of secondary plant products and marked changes in the levels of the minor sugars involved in ascorbate synthesis and cell wall metabolism. Transcript profiling revealed a relatively small number of changes in the levels of transcripts coding for components of redox-regulation, transport processes and cell wall, protein and amino acid metabolism, while there were no major alterations in transcript levels coding for enzymes involved in central metabolic pathways. These results provide a global picture of the effect of redox and reveal the utility of transcript and metabolite profiling as systemic strategies to uncover the occurrence of redox-modulation in vivo. Keywords: redox regulation
2006-04-10 | GSE4021 | GEO
Project description:Investigating the effects of different HMGB1 redox isoforms on macrophage polarization
| PRJNA823691 | ENA
Project description:The cellular redox status plays an essential role in diverse cellular functions, including proliferation, protein homeostasis, and aging. Thus even cells with identical genetic background but different redox status behave differently. Here, we propose a non-laborious and robust methodology to quantify cell-to- cell redox-dependent variability within thousands of cells, detect oxidation levels in cytosol, mitochondria, and peroxisome, and sort cells based on their redox status. We report that cells of the same age have a bi-modular distribution of reduced and oxidized cells starting in the late logarithmic phase. Although the ratio between the oxidized and reduced subpopulations changes during chronological aging, their growth, proteomic and transcriptomic features are conserved during their first days of chronological aging. A comparative proteomic analysis identified three key proteins, Hsp30, Dhh1, and Pnc1, which affect basal oxidation levels and may serve as first line of defense proteins in redox homeostasis.
2018-06-17 | GSE112997 | GEO
Project description:Clostridium thermocellum is a promising CBP candidate organism capable of directly converting lignocellulosic biomass to ethanol. Low yields, productivities and growth inhibition prevent industrial deployment of this organism for commodity fuel production. Symptoms of potential redox imbalance such as incomplete substrate utilization, and fermentation products characteristic of overflow metabolism, have been observed during growth. This perceived redox imbalance may be in part responsible for the mentioned bioproductivity limitations. Toward better understanding the redox metabolism of C. thermocellum, we analyzed gene expression, using microarrays, during addition of two stress chemicals (methyl viologen and hydrogen peroxide) which we observed to change fermentation redox potential. High quality RNA was extracted from C. thermocellum grown on cellobiose in chemostat culture and exposed, separately, to methyl viologen and hydrogen peroxide. Transcriptome profiles were obtained at seven time points during actively growing fermentations, 3 minutes, 15 minutes, 35 minutes, 7 hours, 14 hours, 50 hours, and 60 hours after beginning exposure to each stressor. Exposure treatments were carried out in duplicate and reference/untreated samples were taken before and between treatments, after flushing of stressor chemicals and re-equilibration of growth conditions.
2015-07-29 | E-GEOD-71465 | biostudies-arrayexpress