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Proteomics explored the feasibility of curcumin as anticancer copper ionophore

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Xiang Li

LAB HEAD: Xiang Li

PROVIDER: PXD037337 | Pride | 2022-11-17

REPOSITORIES: Pride

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Proteomics revealed the crosstalk between copper stress and cuproptosis

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

Ionophore 4-Br-A23187 causes copper stress in B. subtilis

Project description:Ionophores are small molecules or peptides that transport metal ions across biological membranes. Their transport capabilities are typically characterized in vitro using vesicles and single ion species. It is difficult to infer from these data which effects ionophores have on living cells in a complex environment (e.g. culture medium), since net transport is influenced e.g. by ion composition, concentration gradients, pH gradient, and active transport. To gain insights into the antibacterial mechanism of the semi-synthetic polyether ionophore 4-Br-A23187, we investigated its effects on the gram-positive model organism Bacillus subtilis. Changes in intracellular ion concentrations were determined using ionomics and the physiological impact was assessed by proteomics. 4-Br-A23187 treatment resulted in an increase in intracellular copper levels, an effect that was dependent on the copper concentration of the medium. The antibiotic effect of 4-Br-A23187 is further aggravated by a decrease in intracellular manganese and magnesium. Effects of copper hyperaccumulation, mirrored by the proteomic response, included oxidative stress, disturbance of proteostasis, metal, and sulfur homeostasis. Especially solvent-exposed iron-sulfur clusters like that of aconitase of the citric acid cycle are readily destabilized by copper. Using calcein fluorescence quenching as a readout, we confirmed in vitro that 4-Br-A23187 acts as copper ionophore.

2022-06-08 | PXD028938 | Pride

Transcription profiling by array of Herminiimonas arsenicoxydans during arsenic stress

Project description:Temporal transcriptomic response during arsenic stress in Herminiimonas arsenicoxydans

2010-09-01 | E-MEXP-2809 | biostudies-arrayexpress

Transcription profiling of Herminiimonas arsenicoxydans reveals transcriptional controls affect arsenite oxidase activity

Project description:view of the global regulation of gene expression in Herminiimonas arsenicoxydans in response to As(III) stress, in particular those coding for arsenite oxidation.

2009-07-01 | E-MEXP-2199 | biostudies-arrayexpress

Y79 retinoblastoma cells: control vs. curcumin treated

Project description:miRNA profiling of curcumin treated Y79 cells with untreated Y79 cells (control). Aim of the study to see whether any oncogenes or tumor suppressor genes are regulated on curcumin treatment in Y79 cells. Agilent one-color experiment,Organism: Human ,Agilent-019118 Human miRNA Microarray 2.0 G4470B , Labeling kit: Agilent miRNA labeling reagent and Hybridization Kit Cat # 5190-0408

2010-04-01 | E-GEOD-21126 | biostudies-arrayexpress

Transcription profiling of human hepatocytes in response to copper overload at nine time points

Project description:Nine time points for microarray analysis were chosen to study early and late transcriptional responses in copper metabolism upon copper overload in HepG2 cells. Samples of copper-treated cells were hybridized using non-treated samples as a reference.

2007-06-01 | E-MEXP-753 | biostudies-arrayexpress

Transcription profiling of heptatocytes from mice given a high-copper diet

Project description:In order to study the physiological consequences of a high-copper diet on hepatic gene expression, 6 mM CuCl2 was added to the drinking water for a period of 1 month. After this period, livers of seven control mice and eight copper-treated mice were isolated and were subjected to microarray analysis and copper measurements. The hepatic gene expression profile of copper-treated mice was compared to non-treated mice using a pooled reference.

2007-06-01 | E-MEXP-745 | biostudies-arrayexpress

Calcium/calmodulin dependent protein kinase kinase 2 (CAMKK2), an alternative to curcumin in head and neck squamous cell carcinoma.

Project description:Curcumin has been shown to exhibit anti-neoplastic effects. However, due to its poor bioavailability, use of curcumin as an anti-cancer drug is limited. It is thus necessary to identify molecules that could be targeted using anti-cancer agents as alternatives to curcumin. For this, it is important to understand the underlying signaling pathways mediating the anti-neoplastic effects of curcumin. We carried out phosphoproteomic analysis (TiO2-based enrichment of Ser/Thr kinases) of head and neck cancer cell line, CAL27 treated with curcumin to identify curcumin mediated signaling pathways. This resulted in the identification of 5921 phosphopeptides (phosphosite probability≥75%) corresponding 1,878 proteins. Of these, 275 and 335 phosphopeptides corresponding to 183 and 242 proteins (≥2.0-fold) were found to be hyper- and hypo-phosphorylated respectively, in response to curcumin treatment

2022-03-03 | PXD007256 | Pride

Phosphotyrosine profiling of curcumin-induced signaling

Project description:Curcumin, derived from the rhizome of Curcuma longa is a natural anti-cancer agent and has been shown to inhibit proliferation and survival of tumor cells. Although the anti-cancer effects of curcumin are well established, detailed understanding of the signaling pathways altered by curcumin is still unclear. In this study, we carried out SILAC-based quantitative proteomic analysis of CAL 27 cell line, a HNSCC cell line to investigate tyrosine signaling in response to curcumin. Using high resolution Orbitrap Fusion™ Tribrid™ Fourier transform mass spectrometer, we identified 627 phosphotyrosine sites mapping to 357 proteins. We observed alterations in the level of phosphorylation of 307 sites corresponding to 204 proteins upon curcumin treatment.

2018-10-24 | PXD002097 | Pride

Copper metabolism in Naegleria gruberi and its deadly relative Naegleria fowleri.

Project description:Although copper is an essential nutrient crucial for many biological processes, an excessive concentration can be toxic and lead to cell death. The metabolism of this two-faced metal must be strictly regulated at the cell level. In this study, we investigated copper homeostasis in two related unicellular organisms: nonpathogenic Naegleria gruberi and the “brain-eating amoeba” Naegleria fowleri. We identified and confirmed the function of their specific copper transporters securing the main pathway of copper acquisition. Adjusting to different environments with varying copper levels during the life cycle of these organisms requires various metabolic adaptations. Using comparative proteomic analyses, measuring oxygen consumption, and enzymatic determination of NADH dehydrogenase, we showed that both amoebas respond to copper deprivation by upregulating the components of the branched electron transport chain: the alternative oxidase and alternative NADH dehydrogenase. Interestingly, analysis of iron acquisition indicated that this system is copper-dependent in N. gruberi but not in its pathogenic relative. Importantly, we identified a potential key protein of copper metabolism of N. gruberi, the homolog of human DJ-1 protein, which is known to be linked to Parkinson’s disease. Altogether, our study reveals the mechanisms underlying copper metabolism in the model amoeba N. gruberi and the fatal pathogen N. fowleri and highlights the differences between the two amoebas.

2022-05-20 | PXD032745 | Pride

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