COMMD10 inhibits HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe balance in hepatocellular carcinoma

Journal of Hepatology, Journal Year: 2022, Volume and Issue: 76(5), P. 1138 - 1150

Published: Jan. 30, 2022

Copper (Cu) is an essential trace element whose serum levels have been reported to act as effective indicator of the efficacy radiotherapy. However, little known about role Cu in In this study we aimed determine and investigate precise mechanism by which or Cu-related proteins regulate radiosensitivity hepatocellular carcinoma (HCC).The expression function copper metabolism MURR1 domain 10 (COMMD10) were assessed via a detection assay, immunostaining, real-time PCR, western blot, radiation clonogenic assay 5-ethynyl-2'-deoxyuridine assay. Ferroptosis was determined detecting glutathione, lipid peroxidation, malondialdehyde ferrous ion (Fe) levels. The vivo effects COMMD10 examined with Cu/Cu chelator treatment lentivirus modification radiated mouse models.We identified novel promoting radioresistance HCC cells. Ionizing (IR) induced reduction COMMD10, increased intracellular led HCC. enhanced ferroptosis vitro vivo. Mechanistically, low IR inhibited ubiquitin degradation HIF1α (by inducing accumulation) simultaneously impaired its combination HIF1α, nuclear translocation transcription ceruloplasmin (CP) SLC7A11, jointly addition, elevated CP promoted reducing Fe, forming positive feedback loop.COMMD10 inhibits HIF1α/CP loop enhance disrupting Cu-Fe homeostasis This work provides new targets strategies for overcoming HCC.Radiotherapy benefits patients unresectable advanced (HCC), but effectiveness hampered radioresistance. Herein, uncovered HCCs. has revealed potential that could be used sensitize

Language: Английский

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Modulation of Intracellular Copper Levels as the Mechanism of Action of Anticancer Copper Complexes: Clinical Relevance

Biomedicines, Journal Year: 2021, Volume and Issue: 9(8), P. 852 - 852

Published: July 21, 2021

Copper (Cu) is a vital element required for cellular growth and development; however, even slight changes in its homeostasis might lead to severe toxicity deleterious medical conditions. Cancer patients are typically associated with higher Cu content serum tumor tissues, indicating increased demand of cancer cells this micronutrient. known readily cycle between the +1 +2 oxidation state biological systems. The mechanism action complexes based on their redox activity induction reactive oxygen species (ROS), leading deadly oxidative stress. However, there number other biomolecular mechanisms beyond ROS generation that contribute anticancer drug candidates. In review, we discuss how interfering intracellular balance via either diet modification or addition inorganic supplements Cu-modulating compounds affects development, progression, sensitivity treatment modalities. We aim provide rationale use Cu-depleting Cu-overloading conditions generate best possible patient outcome minimal toxicity. also advantages pre-formed complexes, such as Cu-(bis)thiosemicarbazones Cu-N-heterocyclic thiosemicarbazones, comparison situ formed metal-binding ligands. summarize available clinical mechanistic data clinically relevant candidates, including supplements, chelators, ionophores, complexes.

Language: Английский

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Prognostic analysis of cuproptosis-related gene in triple-negative breast cancer

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Aug. 1, 2022

Cuproptosis is a copper-dependent cell death mechanism that associated with tumor progression, prognosis, and immune response. However, the potential role of cuproptosis-related genes (CRGs) in microenvironment (TME) triple-negative breast cancer (TNBC) remains unclear.In total, 346 TNBC samples were collected from The Cancer Genome Atlas database three Gene Expression Omnibus datasets, classified using R software packages. relationships between different subgroups clinical pathological characteristics, infiltration mutation status TME examined. Finally, nomogram calibration curve constructed to predict patient survival probability improve applicability CRG_score.We identified two CRG clusters characteristics highly consistent those immune-inflamed immune-desert clusters. Furthermore, we demonstrated gene signature can be used evaluate infiltration, features, prognostic status. Low CRG_scores characterized by high burden activation, good probability, more immunoreactivity CTLA4, while activation stromal pathways immunosuppression.This study revealed effects CRGs on TME, clinicopathological prognosis TNBC. closely immunity are tool for predicting prognosis. Our data provide new directions development novel drugs future.

Language: Английский

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The cuproptosis-related signature associated with the tumor environment and prognosis of patients with glioma

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Aug. 30, 2022

Background Copper ions are essential for cellular physiology. Cuproptosis is a novel method of copper-dependent cell death, and the cuproptosis-based signature glioma remains less studied. Methods Several datasets with clinicopathological information were collected from TCGA, GEO CGGA. Robust Multichip Average (RMA) algorithm was used background correction normalization, cuproptosis-related genes (CRGs) then collected. The TCGA-glioma cohort clustered using ConsensusClusterPlus. Univariate Cox regression analysis Random Survival Forest model performed on differentially expressed to identify prognostic genes. cuproptosis-signature constructed by calculating CuproptosisScore Multivariate analysis. Differences in terms genomic mutation, tumor microenvironment, enrichment pathways evaluated between high- or low-CuproptosisScore. Furthermore, drug response prediction carried out utilizing pRRophetic. Results Two subclusters based CRGs identified. Patients cluster2 had better clinical outcomes. CuproptosisScore. higher WHO grades worse prognosis, while patients lower more likely develop IDH mutations MGMT methylation. demonstrated an independent factor. accuracy further confirmed 11 external validation datasets. In groups high-CuproptosisScore, PIK3CA, MUC16, NF1, TTN, TP53, PTEN, EGFR showed high mutation frequency. IDH1, ATRX, CIC, FUBP1 frequency low-CuproptosisScore group. level immune infiltration increased as increased. SubMap revealed high-CuproptosisScore may respond anti-PD-1 therapy. IC50 values Bexarotene, Bicalutamide, Bortezomib, Cytarabine group than those Finally, importance IGFBP2 confirmed. Conclusion current study might help predict biological features, appropriate treatment glioma.

Language: Английский

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Regulatory roles of copper metabolism and cuproptosis in human cancers

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: March 23, 2023

Copper is an essential micronutrient for human body and plays a vital role in various biological processes including cellular respiration free radical detoxification. Generally, copper metabolism the stable state, there are specific mechanisms to regulate maintain homeostasis. Dysregulation of may have great connection with types diseases, such as Wilson disease causing overload Menkes deficiency. Cancer presents high mortality rates world due unlimited proliferation potential, apoptosis escape immune properties induce organ failure. thought cancer, elevated levels cancer tissue serum. also affects tumor progression by affecting angiogenesis, metastasis other processes. Notably, cuproptosis novel form cell death that provide targeting strategies developing therapy. chelators ionophores two coordinating compounds treatment cancer. This review will explore relationship between cancers, clarify targeted

Language: Английский

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Copper in cancer: from limiting nutrient to therapeutic target

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: June 23, 2023

As an essential nutrient, copper’s redox properties are both beneficial and toxic to cells. Therefore, leveraging the characteristics of copper-dependent diseases or using copper toxicity treat copper-sensitive may offer new strategies for specific disease treatments. In particular, concentration is typically higher in cancer cells, making a critical limiting nutrient cell growth proliferation. Hence, intervening metabolism cells become potential tumor treatment strategy, directly impacting metastasis. this review, we discuss body summarize research progress on role promoting inducing programmed death Additionally, elucidate copper-related drugs treatment, intending provide perspectives treatment.

Language: Английский

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Copper in colorectal cancer: From copper‐related mechanisms to clinical cancer therapies

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(6)

Published: May 28, 2024

Abstract Copper, a trace element and vital cofactor, plays crucial role in the maintenance of biological functions. Recent evidence has established significant correlations between copper levels, cancer development metastasis. The strong redox‐active properties offer both benefits disadvantages to cells. intestinal tract, which is primarily responsible for uptake regulation, may suffer from an imbalance homeostasis. Colorectal (CRC) most prevalent primary tract aggressive malignant disease with limited therapeutic options. Current research focused on relationship CRC. Innovative concepts, such as cuproplasia cuproptosis, are being explored understand copper‐related cellular proliferation death. Cuproplasia regulation cell that mediated by enzymatic nonenzymatic copper‐modulated activities. Whereas, cuproptosis refers death induced excess via promoting abnormal oligomerisation lipoylated proteins within tricarboxylic acid cycle, well diminishing levels iron‐sulphur cluster proteins. A comprehensive understanding mechanisms offers new avenues CRC treatment. In this review, we summarise evolving molecular mechanisms, ranging intracellular concentrations discovered, discuss pathogenesis, progression potential therapies Understanding will help provide theoretical foundation innovative treatment strategies management.

Language: Английский

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Targeting cuproptosis for cancer therapy: mechanistic insights and clinical perspectives

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Aug. 16, 2024

Cuproptosis is a newly identified form of cell death induced by excessive copper (Cu) accumulation within cells. Mechanistically, cuproptosis results from Cu-induced aggregation dihydrolipoamide S-acetyltransferase, correlated with the mitochondrial tricarboxylic acid cycle and loss iron–sulfur cluster proteins, ultimately resulting in proteotoxic stress triggering death. Recently, has garnered significant interest tumor research due to its potential as crucial therapeutic strategy against cancer. In this review, we summarized cellular molecular mechanisms relationship other types Additionally, reviewed current drugs or strategies available induce cells, including Cu ionophores, small compounds, nanomedicine. Furthermore, targeted metabolism specific regulatory genes cancer therapy enhance sensitivity cuproptosis. Finally, discussed feasibility targeting overcome chemotherapy immunotherapy resistance suggested future directions. This study that could open new avenues for developing therapy.

Language: Английский

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AKT1 Phosphorylates FDX1 to Promote Cuproptosis Resistance in Triple‐Negative Breast Cancer

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Abstract Cuproptosis, a recently defined copper‐dependent cell death pathway, remains largely unexplored in tumor therapies, particularly breast cancer. This study demonstrates that triple‐negative cancer (TNBC) bears relatively elevated copper levels and exhibits resistance to cuproptosis. Mechanistically, activates the AKT signaling which inhibits ferredoxin‐1 (FDX1), key regulator of AKT1‐mediated FDX1 phosphorylation not only abrogates FDX1‐induced cuproptosis aerobic respiration but also promotes glycolysis. Consequently, combination AKT1 inhibitors ionophores synergistically alleviate TNBC tumorigenesis both vitro vivo. In summary, findings reveal crucial mechanism underlying suggest potential therapeutic approach for TNBC.

Language: Английский

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The Role of Zinc and Copper in Gynecological Malignancies

Nutrients, Journal Year: 2020, Volume and Issue: 12(12), P. 3732 - 3732

Published: Dec. 3, 2020

Zinc (Zn) and copper (Cu) are essential microelements, which take part in cellular metabolism, feature enzymatic systems, regulate enzyme activity. Homeostasis of these micronutrients is tightly regulated by multiple compensatory mechanisms that balance their concentrations including transporters, importers, metallothioneins. An altered intake only one trace elements may cause an imbalance levels result competition for absorption. Relatively low zinc increased level oxidative stress impair the antioxidant properties enzymes. Altered were discovered various pathologies immunological, degenerative, inflammatory diseases. Moreover, due to role Zn Cu chronic inflammation, they found influence cancerogenesis. We review roles tumor growth, metastasis potential, microenvironment remodeling, drug resistance. highlight as potential biomarkers cancer diagnosis, treatment, prognosis, concentrating on impact gynecological malignancies.

Language: Английский

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