Copper homeostasis and cuproptosis in health and disease

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Ноя. 23, 2022

As an essential micronutrient, copper is required for a wide range of physiological processes in virtually all cell types. Because the accumulation intracellular can induce oxidative stress and perturbing cellular function, homeostasis tightly regulated. Recent studies identified novel copper-dependent form death called cuproptosis, which distinct from other known pathways underlying death. Cuproptosis occurs via binding to lipoylated enzymes tricarboxylic acid (TCA) cycle, leads subsequent protein aggregation, proteotoxic stress, ultimately Here, we summarize our current knowledge regarding metabolism, copper-related disease, characteristics mechanisms that regulate cuproptosis. In addition, discuss implications cuproptosis pathogenesis various disease conditions, including Wilson's neurodegenerative diseases, cancer, therapeutic potential targeting

Язык: Английский

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Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research

Journal of Hematology & Oncology, Год журнала: 2022, Номер 15(1)

Опубликована: Дек. 8, 2022

Abstract Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various activities, including clearance aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target development cancer medications recent years. However, because tumor show avoidance apoptosis, which causes treatment resistance recurrence, numerous studies been devoted alternative mortality processes, namely necroptosis, pyroptosis, ferroptosis, cuproptosis; these modalities extensively studied shown be crucial therapy effectiveness. Furthermore, evidence suggests that undergoing may alter immunogenicity microenvironment (TME) some extent, rendering it more suitable inhibiting progression metastasis. In addition, other components TME undergo abovementioned forms induce immune attacks on cells, resulting enhanced antitumor responses. Hence, this review discusses molecular processes features cuproptosis effects novel proliferation Importantly, introduces complex affect biology. It also summarizes potential agents nanoparticles or inhibit their therapeutic based from vivo vitro reports clinical trials inducers evaluated treatments patients. Lastly, we summarized impact modulating drug advantages adding modulators over conventional treatments.

Язык: Английский

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Copper metabolism in cell death and autophagy

Autophagy, Год журнала: 2023, Номер 19(8), С. 2175 - 2195

Опубликована: Апрель 14, 2023

Copper is an essential trace element in biological systems, maintaining the activity of enzymes and function transcription factors. However, at high concentrations, copper ions show increased toxicity by inducing regulated cell death, such as apoptosis, paraptosis, pyroptosis, ferroptosis, cuproptosis. Furthermore, can trigger macroautophagy/autophagy, a lysosome-dependent degradation pathway that plays dual role regulating survival or death fate cells under various stress conditions. Pathologically, impaired metabolism due to environmental genetic causes implicated variety human diseases, rare Wilson disease common cancers. Therapeutically, copper-based compounds are potential chemotherapeutic agents be used alone combination with other drugs approaches treat cancer. Here, we review progress made understanding metabolic processes their impact on regulation autophagy. This knowledge may help design future clinical tools improve cancer diagnosis treatment.

Язык: Английский

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Cuproptosis Induced by ROS Responsive Nanoparticles with Elesclomol and Copper Combined with αPD‐L1 for Enhanced Cancer Immunotherapy

Advanced Materials, Год журнала: 2023, Номер 35(22)

Опубликована: Март 14, 2023

Cuproptosis is a new cell death that depends on copper (Cu) ionophores to transport Cu into cancer cells, which induces death. However, existing are small molecules with short blood half-life making it hard enough cells. Herein, reactive oxygen species (ROS)-sensitive polymer (PHPM) designed, used co-encapsulate elesclomol (ES) and form nanoparticles (NP@ESCu). After entering ES Cu, triggered by excessive intracellular ROS, readily released. work in concerted way not only kill cells cuproptosis, but also induce immune responses. In vitro, the ability of NP@ESCu efficiently cuproptosis investigated. addition, change transcriptomes treated explored RNA-Seq. vivo, found mice model subcutaneous bladder cancer, reprograming tumor microenvironment. Additionally, further combined anti-programmed protein ligand-1 antibody (αPD-L1). This study provides first report combining nanomedicine can αPD-L1 for enhanced therapy, thereby providing novel strategy future therapy.

Язык: Английский

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Ferroptosis inducers enhanced cuproptosis induced by copper ionophores in primary liver cancer

Journal of Experimental & Clinical Cancer Research, Год журнала: 2023, Номер 42(1)

Опубликована: Июнь 6, 2023

Cuproptosis and ferroptosis are the two newly defined metal-related regulated cell death. However, crosstalk between cuproptosis is obscure.We analyzed effect of inducers on copper ionophores-induced death through CCK-8 assay. was studied using immunofluorescence protein soluble-insoluble fraction isolation. GSH assay, qRT-PCR western blot were adopted to explore machinery enhanced cuproptosis. And mouse xenograft model built detect synergy elesclomol-Cu sorafenib in vivo.Herein we found that erastin could enhance primary liver cancer cells by increasing dependent lipoylated aggregation. Mechanically, upregulated lipoylation via suppressing mitochondrial matrix-related proteases mediated ferredoxin 1 (FDX1) degradation, reduced intracellular chelator glutathione (GSH) synthesis inhibiting cystine importing.Our findings proposed combination ionophores co-targeting be a novel therapeutic strategy for cancer.

Язык: Английский

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Biofilm Microenvironment‐Responsive Self‐Assembly Nanoreactors for All‐Stage Biofilm Associated Infection through Bacterial Cuproptosis‐like Death and Macrophage Re‐Rousing

Advanced Materials, Год журнала: 2023, Номер 35(36)

Опубликована: Июнь 1, 2023

Bacterial biofilm-associated infections (BAIs) are the leading cause of prosthetic implant failure. The dense biofilm structure prevents antibiotic penetration, while highly acidic and H2 O2 -rich microenvironment (BME) dampens immunological response antimicrobial macrophages. Conventional treatments that fail to consistently suppress escaping planktonic bacteria from result in refractory recolonization, allowing BAIs persist. Herein, a BME-responsive copper-doped polyoxometalate clusters (Cu-POM) combination with mild photothermal therapy (PTT) macrophage immune re-rousing for BAI eradication at all stages is proposed. self-assembly Cu-POM BME converts endogenous toxic ·OH through chemodynamic (CDT) generates PTT effect induce bacterial metabolic exuberance, resulting loosening membrane bacteria, enhancing copper transporter activity increasing intracellular flux. Metabolomics reveals overload restricts TCA cycle peroxide accumulation, promoting cuproptosis-like death. CDT macrophages scavenge disintegration enhanced chemotaxis phagocytosis. Overall, promotes death via interference, also further elimination, all-stage clearance providing new reference future clinical application.

Язык: Английский

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Ferroptosis as a potential target for cancer therapy

Cell Death and Disease, Год журнала: 2023, Номер 14(7)

Опубликована: Июль 24, 2023

Abstract Ferroptosis is a recently discovered essential type of cell death that mainly characterized by iron overload and lipid peroxidation. Emerging evidence suggests ferroptosis double-edged sword in human cancer. However, the precise underlying molecular mechanisms their differential roles tumorigenesis are unclear. Therefore, this review, we summarize briefly present key pathways ferroptosis, paying special attention to regulation as well its dual role an oncogenic tumor suppressor event various cancers. Moreover, multiple pharmacological activators summarized, prospect targeting cancer therapy further elucidated.

Язык: Английский

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Cuproptosis: A novel therapeutic target for overcoming cancer drug resistance

Drug Resistance Updates, Год журнала: 2023, Номер 72, С. 101018 - 101018

Опубликована: Ноя. 11, 2023

Cuproptosis is a newly identified form of cell death driven by copper. Recently, the role copper and triggered in pathogenesis cancers have attracted attentions. has garnered enormous interest cancer research communities because its great potential for therapy. Copper-based treatment exerts an inhibiting tumor growth may open door chemotherapy-insensitive tumors. In this review, we provide critical analysis on homeostasis dysregulation development progression cancers. Then core molecular mechanisms cuproptosis discussed, followed summarizing current understanding copper-based agents (copper chelators, ionophores, complexes-based dynamic therapy) treatment. Additionally, summarize emerging data ionophores to subdue chemotherapy resistance different types We also review small-molecule compounds nanoparticles (NPs) that kill cells inducing cuproptosis, which will shed new light anticancer drugs through future. Finally, important concepts pressing questions future should be focused were discussed. This article suggests targeting could novel antitumor therapy strategy overcome drug resistance.

Язык: Английский

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Aggregation‐induced emission luminogens for in vivo molecular imaging and theranostics in cancer

Aggregate, Год журнала: 2023, Номер 4(5)

Опубликована: Май 6, 2023

Abstract Cancer is one of the most fatal diseases for decades. Aggregation‐induced emission luminogens (AIEgens) have been recently used as molecular imaging or therapeutic agents in cancers, due to advantages large Stokes shift, high quantum yield, great biocompatibility, and strong photostability. AIEgens can specifically target different types cancer via diverse targeting strategies. AIEgen‐based fluorescence imaging, especially near‐infrared demonstrated deep penetration suitable signal‐to‐noise ratio, which allows reliable vivo imaging. Combined with other modalities, multimodal could provide multidimensional hallmarks from perspectives. In addition, phototherapy be photodynamic therapy photothermal therapy, facilitate ablation cells good biosafety effects vivo. nanoparticles fabricated some specific chemicals, drugs, siRNA, display synergistic cancers. This paper comprehensively describes current status future perspectives AIEgens, showed a potential preclinical clinical translation on theranostics cancer.

Язык: Английский

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4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to promote cuproptosis in colorectal cancer

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 159, С. 114301 - 114301

Опубликована: Янв. 25, 2023

Cuproptosis, a novel copper-induced cell death pathway, is linked to mitochondrial respiration and mediated by protein lipoylation. The discovery of cuproptosis unfolds new areas investigation, particularly in cancers. present study aimed explore the role colorectal cancer progression. genetic alterations colon were evaluated using database. MTT assays, colony formation, flow cytometry used examine effect elesclomol-Cu 4-Octyl itaconate (4-OI) on oxaliplatin-resistant viability. anti-tumor elesclomol with 4-OI was verified vivo assay. results showed that FDX1, SDHB, DLAT, DLST genes more highly expressed normal tissues than those primary tumor tissues. Patients high expressions these had better prognosis. Using assay formation analysis, pulse treatment significant inhibition viability HCT116, LoVo, HCT116-R cells. In addition, revealed significantly promoted apoptosis. Tetrathiomolybdate, copper chelator, markedly inhibited cuproptosis. Subsequently, we found 2-deoxy-D-glucose, glucose metabolism inhibitor, sensitized Furthermore, galactose further Interestingly, enhanced which irrelevant ROS production, apoptosis, necroptosis, or pyroptosis pathways. Aerobic glycolysis through GAPDH, one key enzymes glycolysis, sensitizing Meanwhile, FDX1 knockdown weakened ability promote experiments, effects. These indicated rapidly halted growth cells line. Importantly, aerobic targeting GAPDH

Язык: Английский

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