Proteomic validation of cell death mechanisms of HDQ-mediated copper transporting
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Xiang Li
PROVIDER: PXD075646 | iProX | Fri Mar 13 00:00:00 GMT 2026
REPOSITORIES: iProX
Similar Datasets
Project description:As an essential micronutrient element in organisms, copper controls a host of fundamental cellular functions. Recently, copper-dependent cell growth and proliferation have been defined as "cuproplasia". Conversely, “cuproptosis” represents copper-dependent cell death, a nonapoptotic manner. So far, a series of copper ionophores have been developed to kill cancer cells. However, the biological response mechanism of copper uptake still lacks systematic analysis. Based on quantitative proteomics, we revealed the crosstalk between copper stress and cuproptosis in cancer cells. Copper stress not only couples with cuproptosis, but also leads to reactive oxygen species (ROS) stress, oxidative damage and cell cycle arrest. In cancer cells, a feedback cytoprotection mechanism involving cuproptosis mediators was discovered. During copper treatment, the activation of glutamine transporters and the loss of Fe-S cluster proteins are the facilitators and results of cuproptosis, respectively. Through copper depletion, glutathione (GSH) blocks the cuproptosis process, rescues the activation of glutamine transporters, and prevents the loss of Fe-S cluster proteins, expect for protecting cancer cells from apoptosis, protein degradation and oxidative damage. Our results are significative for understanding cuproptosis process and developing novel anticancer reagents based on cuproptosis.
2022-11-17 | PXD037278 | Pride
Project description:Copper-related cell death, cuproptosis, involves accumulation of intracellular copper that triggers mitochondrial lipoylated protein aggregation and destabilization of iron–sulfur cluster proteins. Here, glioblastoma (GBM) stem cells (GSCs) displayed resistance to cuproptosis with circadian variation of intracellular copper levels, unlike differentiated GBM cells (DGCs) or neural stem cells (NSCs). CRISPR screening of copper regulators under concurrent treatment with copper ionophore or clock disruption revealed dependency on ATPase Copper Transporting Alpha (ATP7A). Circadian control of copper homeostasis was mediated by core clock transcription factor, Basic helix-loop-helix ARNT-like protein 1 (BMAL1). In turn, ATP7A promoted tumor cell growth through regulation of fatty acid desaturation. Copper levels negatively fed back onto the circadian clock through SQSTM1 (sequestosome 1/p62)-mediated lysosomal degradation of BMAL1. Targeting cuproptosis and circadian clock or fatty acid desaturation generated synergistic anti-tumor effects. Thus, crosstalk between the circadian rhythm and copper sustains GSCs, reshaping fatty acid metabolism and promoting drug resistance.
2025-10-14 | GSE278671 | GEO
Project description:As an essential micronutrient element in organisms, copper controls a host of fundamental cellular functions. Recently, copper-dependent cell growth and proliferation have been defined as "cuproplasia". Conversely, “cuproptosis” represents copper-dependent cell death, a nonapoptotic manner. So far, a series of copper ionophores have been developed to kill cancer cells. However, the biological response mechanism of copper uptake still lacks systematic analysis. Based on quantitative proteomics, we explored the feasibility of curcumin as anticancer copper ionophore. The copper ionophore curcumin can control the metabolisms of lipids, RNA, NADH and NADPH in colorectal cancer cells, and also up-regulates positive cuproptosis mediators. This work discolored the suppression and acceleration of cuproptosis by GSH and curcumin, respectively. Our results are significative for understanding cuproptosis process and developing novel anticancer reagents based on cuproptosis.
2022-11-17 | PXD037337 | Pride
Project description:Copper and iron are essential micronutrients for most living organisms because they participate as cofactors in biological processes including respiration, photosynthesis and oxidative stress protection. In many eukaryotic organisms, including yeast and mammals, copper and iron homeostases are highly interconnected; however such interdependence is not well established in higher plants. Here we propose that COPT2, a high-affinity copper transport protein, functions under copper and iron deficiencies in Arabidopsis thaliana. COPT2 is a plasma membrane protein that functions in copper acquisition and distribution. Characterization of the COPT2 expression pattern indicates a synergic response to copper and iron limitation in roots. We have characterized a knockout of COPT2, copt2-1, that leads to increased resistance to simultaneous copper and iron deficiencies, measured as reduced leaf chlorosis and improved maintenance of the photosynthetic apparatus. We propose that COPT2 expression could play a dual role under Fe deficiency. First, COPT2 participates in the attenuation of copper deficiency responses driven by iron limitation maybe aimed to minimize further iron consume. On the other hand, global expression analyses of copt2-1 mutants versus wild type Arabidopsis plants indicate that low phosphate responses are increased in copt2-1 plants. In this sense, COPT2 function under Fe deficiency counteracts low phosphate responses. These results open up new biotechnological approaches to fight iron deficiency in crops. Four biological replicates of Arabidopsis seedlings were generated for 2 genotypes, Col-0 and copt2-1 mutant; and 3 growth condictions; first one an iron(Fe) and copper(Cu) sufficient medium (+Fe + Cu), second one an Fe deficient and Cu sufficient medium (-Fe+Cu) and third one an Fe and Cu deficient medium (-Fe-Cu). For each growth one comparasion was made, copt2-1 mutant versus Col-0; in each comparasion four biological replicates were made, two replicas were labeled with Cy5 for the mutant sample and Cy3 for the Col-0 sample, while the other two replicas were reversed-labeled.
2013-06-05 | E-GEOD-42642 | biostudies-arrayexpress
Project description:Copper and iron are essential micronutrients for most living organisms because they participate as cofactors in biological processes including respiration, photosynthesis and oxidative stress protection. In many eukaryotic organisms, including yeast and mammals, copper and iron homeostases are highly interconnected; however such interdependence is not well established in higher plants. Here we propose that COPT2, a high-affinity copper transport protein, functions under copper and iron deficiencies in Arabidopsis thaliana. COPT2 is a plasma membrane protein that functions in copper acquisition and distribution. Characterization of the COPT2 expression pattern indicates a synergic response to copper and iron limitation in roots. We have characterized a knockout of COPT2, copt2-1, that leads to increased resistance to simultaneous copper and iron deficiencies, measured as reduced leaf chlorosis and improved maintenance of the photosynthetic apparatus. We propose that COPT2 expression could play a dual role under Fe deficiency. First, COPT2 participates in the attenuation of copper deficiency responses driven by iron limitation maybe aimed to minimize further iron consume. On the other hand, global expression analyses of copt2-1 mutants versus wild type Arabidopsis plants indicate that low phosphate responses are increased in copt2-1 plants. In this sense, COPT2 function under Fe deficiency counteracts low phosphate responses. These results open up new biotechnological approaches to fight iron deficiency in crops.
2013-06-05 | GSE42642 | GEO
Project description:Cuproptosis is characterized by the aggregation of lipoylated components of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. Dysregulation of copper homeostasis and resulting cuproptosis induction is an emerging area of interest for cancer therapy. However, mechanisms of cancer cell evasion of cuproptosis are not well understood. Here, we found that the cuproptosis process is accompanied by activation of the Wnt/β-catenin pathway. Mechanistically, copper binds to PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/β-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/β-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed that the β-catenin/TCF4 transcriptional complex directly binds to the promoter region of ATP7B, a protein responsible for the efflux of copper ions from the cell, inducing its expression and reducing intracellular copper accumulation, thereby inhibiting cuproptosis. Knockdown of TCF4 or pharmacological blockade of the Wnt/β-catenin pathway increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/β-catenin pathway and cuproptosis sensitivity, and may provide a precision medicine strategy for cancer treatment by selectively inducing cuproptosis
2023-11-21 | GSE248084 | GEO
Project description:Cuproptosis is characterized by the aggregation of lipoylated components of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. Dysregulation of copper homeostasis and resulting cuproptosis induction is an emerging area of interest for cancer therapy. However, mechanisms of cancer cell evasion of cuproptosis are not well understood. Here, we found that the cuproptosis process is accompanied by activation of the Wnt/β-catenin pathway. Mechanistically, copper binds to PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/β-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/β-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed that the β-catenin/TCF4 transcriptional complex directly binds to the promoter region of ATP7B, a protein responsible for the efflux of copper ions from the cell, inducing its expression and reducing intracellular copper accumulation, thereby inhibiting cuproptosis. Knockdown of TCF4 or pharmacological blockade of the Wnt/β-catenin pathway increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/β-catenin pathway and cuproptosis sensitivity, and may provide a precision medicine strategy for cancer treatment by selectively inducing cuproptosis
2023-11-21 | GSE248083 | GEO
Project description:Cuproptosis is characterized by copper ion-induced polymerization of lipoylated proteins. Whether other proteins involved in cuprotosis also undergo polymerization in the presence of copper ions remains to be determined. In this study, we utilized three experimental approaches to identify novel copper-induced polymerized proteins associated with cuprotosis. In the first two approaches, melanoma A375 cells were treated with copper ionophores—either elesclomol (ES) or disulfiram (DSF) in combination with copper—prior to cell lysis. In the third approach, cell lysates were directly incubated with copper ions in vitro. The resulting lysates were then subjected to non-reducing gel electrophoresis to detect proteins that undergo copper-induced polymerization. We expect to identify new target proteins of copper ions and new participating and executing proteins of copper death through this method.
2026-04-25 | PXD076672 | Pride
Project description:A 3 x 2 factorial design was used to elucidate the genome-wide transcriptional response to the deletion of yeast ortholog of Wilson and Menkes disease causing gene; CCC2, at changing copper levels. Homozygous deletion mutant of CCC2, which encodes Cu+2 transporting P-type ATPase required to export copper from the cytosol into the extracytosolic compartment, and the reference strain were cultivated in fully controlled fermenters in duplicates in glucose-rich defined medium containing three different levels of copper. The three different copper concentrations were selected such that; copper deficient condition, which was prepared by excluding the CuSO4.7H2O from the defined medium, low copper or adequate copper concentration, which is the standard amount of copper in defined medium (0.04 ?M) and high copper concentration (0.5 mM), which was able to restore respiration deficiency in ccc2?/ccc2? strain.
2013-09-02 | E-MEXP-3927 | biostudies-arrayexpress
Project description:Wilson disease (WD) is a severe metabolic disorder caused by genetic inactivation of copper-transporting ATPase ATP7B. In WD, copper accumulates in several tissues, particularly in the liver, inducing marked time-dependent pathological changes. To identify initial events in the copper-dependent development of liver pathology we utilized the Atp7b-/- mice, an animal model for WD. Analysis of mRNA from livers of control and Atp7b-/- 6 weeks-old mice using oligonucleotide arrays revealed specific changes of the transcriptome at this stage of copper accumulation. Few messages (29 up-regulated and 46 down-regulated) change their abundance more than 2-fold pointing to the specific effect of copper on gene expression/mRNA stability. The gene ontology analysis revealed copper effects on distinct metabolic pathways. Keywords: comparative genomic hybridization
2006-12-19 | GSE5348 | GEO