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Cancer cells reprogram their copper metabolism to adapt to adverse microenvironments, such as oxidative stress. The copper chelator elesclomol has been reported to have considerable anticancer efficacy, but the underlying mechanisms remain largely unknown. In this study, we found that elesclomol‐mediated copper overload inhibits colorectal cancer (CRC) both in vitro and in vivo. Elesclomol alone promotes the degradation of the copper transporter copper‐transporting ATPase 1 (ATP7A), which retards the proliferation of CRC cells. This property distinguishes it from several other copper chelators. Combinational treatment of elesclomol and copper leads to copper retention within mitochondria due to ATP7A loss, leading to reactive oxygen species accumulation, which in turn promotes the degradation of SLC7A11, thus further enhancing oxidative stress and consequent ferroptosis in CRC cells. This effect accounts for the robust antitumour activity of elesclomol against CRC, which can be reversed by the administration of antioxidants and ferroptosis inhibitors, as well as the overexpression of ATP7A. In summary, our findings indicate that elesclomol‐induced copper chelation inhibits CRC by targeting ATP7A and regulating ferroptosis. In this study, we describe the molecular mechanisms by which elesclomol‐mediated copper (Cu2+) overload inhibits colorectal cancer (CRC) both in vitro and in vivo. Elesclomol elevated Cu2+ levels in mitochondria and decreased the expression of the Cu2+ transporter ATP7A, leading to Cu2+ retention and the subsequent accumulation of reactive oxygen species. The process promoted the degradation of SLC7A11, which further enhanced oxidative stress and induced ferroptosis in CRC cells.

Background: Cancer resistance to chemotherapy is closely associated with changes in transporter systems. In this study, we investigated the possible regulation of 1 copper ion transporter (ATP7A; ATPase copper transporting alpha) by microRNA miR-495 and its implications in cisplatin resistance and angiogenesis in esophageal cancer. Methods: MiR-495 and ATP7A mRNA expression in clinical tissue samples and 2 cancer cell lines (Eca-109 and TE1) were detected by quantitative real-time polymerase chain reaction. The levels of miR-495 and ATP7A expression in Eca-109 and TE1 cells were increased by transfection with miR-495 mimics and ATP7A-overexpression vectors. Cell proliferation, apoptosis, and angiogenesis were assessed by CCK-8, flow cytometry, and tube formation assays, respectively. The levels of TNF-α and VEGF in cell culture supernatants were detected by enzyme linked immunosorbent assay, and in situ expression of NLRP3 was measured by immunofluorescence. The binding of miR-495 to ATP7A sequences was verified by dual luciferase reporter assays. Results:ATP7A expression was significantly increased, while miR-495 expression was decreased in the cancer tissues of esophageal cancer patients. MiR-495 mimics decreased the proliferation and promoted the apoptosis of cisplatin-resistant Eca-109 and TE1 cells. Furthermore, tube formation by human umbilical vein endothelial cells, TNF-α and VEGF secretion, and the levels of MRP1, ABCG1, ABCA1, and NLRP3 expression in cisplatin-resistant Eca-109 and TE1 cells were all reduced by miR-495 mimics. MiR-495 was shown to directly bind to ATP7A gene sequences to repress ATP7A expression in Eca-109 and TE1 cells. ATP7A overexpression substantially abrogated the changes in proliferation, apoptosis, angiogenesis, and above-mentioned gene expression in cisplatin-resistant Eca-109 and TE1 cells. Conclusions: MiR-495 suppressed cisplatin resistance and angiogenesis in esophageal cancer cells by targeting ATP7A gene expression.

To investigate the link between UVB-induced skin photodamage and cuproptosis, and identify key regulatory genes. Transcriptomic data from UVB-irradiated human skin (GSE41078) were obtained from GEO. Differentially expressed genes (DEGs) were identified, followed by GO and KEGG enrichment, and WGCNA. Key regulators were defined by intersecting DEGs, cuproptosis-related genes (CRGs), and the WGCNA module most correlated with photodamage. Single-cell RNA-seq data (GSE289389) were used to assess ATP7A expression in keratinocytes and to infer cell-cell communication (CellChat), focusing on ECM and adhesion signaling. Hub genes were validated via qRT-PCR and Western blot in UVB-induced acute photodamage cells and mouse models. Examination of the GSE41078 dataset revealed 509 DEGs associated with photodamage. WGCNA identified the blue module as most strongly correlated with photodamage. Cross-referencing 978 core module genes with 55 CRGs and 509 DEGs identified a single hub gene, ATPase copper transporting alpha (ATP7A). Single-cell analysis confirmed significant ATP7A downregulation after UVB exposure (p = 1.83 × 10 ) and showed that ATP7A-high keratinocytes exhibited stronger integration with stromal cells via enhanced ECM-adhesion signaling (e.g. collagen, laminin), whereas ATP7A-low cells displayed weakened responsiveness to microenvironmental cues. Experimental confirmation suggested that both mRNA and protein expression of ATP7A were markedly diminished in photodamaged cellular and mouse models (P < 0.05), aligning with the computational predictions. This study suggests a potential association between ATP7A downregulation and UVB-induced photodamage with possible relevance to cuproptosis-related pathways. ATP7A downregulation is associated with reduced ECM-adhesion signaling interactions in keratinocytes, as indicated by CellChat. This analysis provides new clues to the mechanism of photodamage and suggests that ATP7A may be involved in the functional regulation of skin photodamage.

Menkes disease (MD) is a lethal multisystemic disorder of copper metabolism. Progressive neurodegeneration and connective tissue disturbances, together with the peculiar ‘kinky’ hair are the main manifestations. MD is inherited as an X-linked recessive trait, and as expected the vast majority of patients are males. MD occurs due to mutations in the ATP7A gene and the vast majority of ATP7A mutations are intragenic mutations or partial gene deletions. ATP7A is an energy dependent transmembrane protein, which is involved in the delivery of copper to the secreted copper enzymes and in the export of surplus copper from cells. Severely affected MD patients die usually before the third year of life. A cure for the disease does not exist, but very early copper-histidine treatment may correct some of the neurological symptoms.

Human SNCA , which encodes a-synuclein protein ( SNCA ), was the first gene linked to familial Parkinson’s disease (PD). Since the discovery of the genetic link of SNCA to Parkinson’s nearly three decades ago, many studies have investigated the normal function of SNCA protein. However, understanding of the normal function of SNCA is complicated by the lack of a reliable mammalian model of PD; indeed, mice with homozygous null mutations in the Snca gene live a normal lifespan and have only subtle synaptic deficits. Here, we report the first genetic modifier (a sensitized mutation) of a murine Snca null mutation, namely the ATPase copper transporting alpha (Atp7a), an X-linked gene that escapes inactivation in both mice and humans. In humans, mutations in Atp7a are linked to Menkes disease, a disease with pleiotropic and severe neurological phenotypes. Atp7a encodes a copper transporter that supplies the copper co-factor to enzymes that pass through the ER-Golgi network; under some conditions, Atp7a protein may also act to increase copper flux across the cell membrane. Male mice that carry a mutation in Atp7a die within 3 weeks of age regardless of Snca genotype. In contrast, female mice that carry the Atp7a mutation, on an Snca null background, die earlier (prior to 35 days) at a significantly higher rate than those that carry the Atp7a mutation on a wildtype Snca background. Thus, Snca null mutations sensitize female mice to mutations in Atp7a, suggesting that Snca protein may have a protective effect in females, perhaps in neurons, given the co-expression patterns. This study adds to the growing literature suggesting that alterations in a-synuclein structure and/or quantity may manifest in neurological differences in males and females including phenotypes of developmental delays, seizures, muscle weakness and cognitive function.

Copper ions are needed for several hallmarks of cancer. However, the involved pathways, mechanisms, and copper-binding proteins are mostly unknown. We recently found that cytoplasmic Antioxidant 1 copper chaperone (Atox1), which is up-regulated in breast cancer, is localized at the lamellipodia edges of aggressive breast cancer cells. To reveal molecular insights into a putative role in cell migration, we here investigated breast cancer cell (MDA-MB-231) migration by video microscopy as a function of Atox1. Tracking of hundreds of individual cells (per condition) over a 9-h time series revealed that cell migration velocity and directionality are significantly reduced upon Atox1 silencing in the cells. Because silencing of the copper transporter ATP7A also reduced cell migration, these proteins appear to be on the same pathway, suggesting that their well-known copper transport activity is involved. In-cell proximity ligation assays demonstrated that Atox1, ATP7A, and the proenzyme of lysyl oxidase (LOX; copper-loaded via ATP7A) are all in close proximity and that LOX activity is reduced upon Atox1 silencing in the cells. Since LOX is an established player in cancer cell migration, our results imply that Atox1 mediates breast cancer cell migration via coordinated copper transport in the ATP7A-LOX axis. Because individual cell migration is an early step in breast cancer metastasis, Atox1 levels in tumor cells may be a predictive measure of metastasis potential and serve as a biomarker for copper depletion therapy.

Over the past two decades there have been significant advances in our understanding of copper homeostasis and the pathological consequences of copper dysregulation. Cumulative evidence is revealing a complex regulatory network of proteins and pathways that maintain copper homeostasis. The recognition of copper dysregulation as a key pathological feature in prominent neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases has led to increased research focus on the mechanisms controlling copper homeostasis in the brain. The copper-transporting P-type ATPases (copper-ATPases), ATP7A and ATP7B, are critical components of the copper regulatory network. Our understanding of the biochemistry and cell biology of these complex proteins has grown significantly since their discovery in 1993. They are large polytopic transmembrane proteins with six copper-binding motifs within the cytoplasmic N-terminal domain, eight transmembrane domains, and highly conserved catalytic domains. These proteins catalyze ATP-dependent copper transport across cell membranes for the metallation of many essential cuproenzymes, as well as for the removal of excess cellular copper to prevent copper toxicity. A key functional aspect of these copper transporters is their copper-responsive trafficking between the trans-Golgi network and the cell periphery. ATP7A- and ATP7B-deficiency, due to genetic mutation, underlie the inherited copper transport disorders, Menkes and Wilson diseases, respectively. Their importance in maintaining brain copper homeostasis is underscored by the severe neuropathological deficits in these disorders. Herein we will review and update our current knowledge of these copper transporters in the brain and the central nervous system, their distribution and regulation, their role in normal brain copper homeostasis, and how their absence or dysfunction contributes to disturbances in copper homeostasis and neurodegeneration.

One of the hallmarks of Cu metabolism in mammals is that tissue and fluid levels are normally maintained within a very narrow range of concentrations. This results from the ability of the organism to respond to variations in intake from food and drink by balancing excretion, which occurs mainly via the bile and feces. Although this sounds straightforward and we have already learned a great deal about aspects of this process, the balance between overall intake and excretion occurs over a high background of Cu recycling, which has generally been ignored. In fact, most of the Cu absorbed from the GI tract actually comes from digestive fluids and is constantly “re-used”. A great deal more recycling of Cu probably occurs in the interior, between cells of individual tissues and the fluid of the blood and interstitium. This review presents what is known that is pertinent to understanding these complexities of mammalian Cu homeostasis and indicates where further studies are needed.

Circular RNAs (circRNAs) are a class of non-coding RNAs with a unique covalently closed loop structure. Recent studies indicate that dysregulation of circRNAs acts a role in cancer progression and chemotherapy resistance via interacting with RNA-binding proteins (RBPs). Herein, we identified circPBX3 to be involved in cisplatin resistance of ovarian cancer. In our study, two cisplatin-resistant ovarian cancer cell lines were established, and transcriptome RNA-sequencing was performed and circPBX3 was identified as significantly upregulated circRNA in these cells. The characteristics of circPBX3 and potential function of circPBX3 were evaluated. We found that circPBX3 was upregulated in ovarian tumor tissues and cisplatin-resistant ovarian cancer cells. CircPBX3 overexpression increased the half maximal inhibitory rate (IC50) of cisplatin, promoted colony formation and tumor xenografts growth, and reduced cell apoptosis of ovarian cancer cells under cisplatin treatment, while silencing circPBX3 showed opposite effects. Furthermore, circPBX3 could interact with the RNA-binding protein IGF2BP2, thus increased the stability of ATP7A mRNA and elevated ATP7A protein level. In addition, silencing ATP7A in ovarian cancer cells abrogated the effect of circPBX3 overexpression on cisplatin tolerance. Our findings provided a novel role of circPBX3 in cisplatin resistance of ovarian cancer.

Background Menkes Disease (MD) is a fatal X-linked recessive disorder caused by mutations in the ATP7A gene. Severe cases typically die before the age of three. Mild MD and occipital horn syndrome are variants of MD characterized by a less severe phenotype and longer survival. Objective This case series aims to validate previous findings, expand the clinical phenotype, identify novel ATP7A mutations of MD patients. Methods Observational data with follow-up were collected from 17 genetically diagnosed Chinese MD patients. Results All 17 patients exhibited neurological symptoms, including delayed motor milestones (100%) and seizures (58.8%). Unspecific pregnancy or delivery complications occurred in 9 patients (52.9%). The most prevalent connective tissue problems were abnormal hair (76.5%), followed by skeletal and dental abnormalities (52.9%), skin problems (41.2%) and hernia (35.3%). Sensorineural hearing loss (17.6%) was previously unreported. Coronary artery aneurysm and patent foramen ovale (5.9%) were infrequent. One 16-year-old boy carries pathological exon 3–4 deletion, presents novel mild phenotype including short stature and cerebellar ataxia. Out of 13 patients with follow-up (median: 24 months), 7 patients (53.8%) died with median survival of 40 months (range: 21–48 months), 3 patients (23.1%) show severe motor development delay and 2 (15.4%) have refractory epilepsy, only the mild MD patient shows improved cerebellar ataxia. Sixteen ATP7A mutations were identified including 6 small indels (37.5%), 5 nonsense mutations (31.2%), 2 missense mutations (12.5%), 2 exon deletions (12.5%), and 1 splice site mutation (6.25%). Fourteen mutations were novel. Conclusions Our study further broadens the phenotypic and genotypic spectrums of Menkes disease.