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Activation of Lysosomal Exocytosis Improves Delivery of Most-Frequent WD-Causing ATP7B H1069Q Mutant to the Cell Surface (A) Control HeLa cells and CF7 cells were infected with adeno-ATP7B H1069Q-GFP, incubated with 200 mM CuSO 4 for 2 hr, and stained for LAMP1 and TGN 46. Open and solid arrows show Golgi and lysosomes, respectively. (B) Control HeLa and CF7 cells were treated as in (A), fixed, and processed for immunogold EM to reveal ATP7B H1069Q distribution. Although ATP7B H1069Q was mistargeted to the ER (arrows), it can be detected also in the Golgi (empty arrow) and lysosomes (empty arrowheads). Filled arrowheads indicate higher amount of ATP7B H1069Q at the surface of CF7 cells. (C) Quantification revealed increase in the percentage of ATP7B-associated gold particles (average ± SD; n = 30 cells) at the plasma membrane in CF7 cells.
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Copper is an essential yet toxic metal and its overload causes Wilson disease, a disorder due to mutations in copper transporter ATP7B. To remove excess copper into the bile, ATP7B traffics toward canalicular area of hepatocytes. However, the trafficking mechanisms of ATP7B remain elusive. Here, we show that, in response to elevated copper, ATP7B m...
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... of Lysosomal Exocytosis Accelerates Cell Surface Delivery of the Most Frequent Wilson-Disease- Causing ATP7B Mutant Finally, we determined whether activation of lysosomal exocy- tosis could be utilized as a therapeutic strategy to contrast Wilson disease (WD) pathogenesis. The most frequent ATP7B mutant H1069Q (up to 50% in Caucasian population; Payne et al., 1998), exhibits residual catalytic activity (van den Berghe et al., 2009) but is retained within the endoplasmic reticulum (ER), where it undergoes degradation (Payne et al., 1998; van (legend continued on next page) Developmental Cell ATP7B-Driven Lysosome Exocytosis in Cu Homeostasis den Berghe et al., 2009). Thus, correction of this mutant to the regular functional compartment might be beneficial for the large cohort of the WD patients. Interestingly, despite extensive re- tention within the ER (Figures 8A and 8B, arrows), some ATP7B H1069Q gets transported to the Golgi (empty arrows in Fig- ures 8A and 8B) and further to LAMP1-positive structures (Fig- ure 8A, solid arrows). Thus, we reasoned that acceleration of lysosomal exocytosis might allow a more-efficient supply of re- sidual ATP7B H1069Q to the cell surface, where it can transport Cu out of the cell. To test this, TFEB-overexpressing CF7 cells were infected with an adenovirus carrying ATP7B H1069Q and exposed to CuSO 4 . Arrows in Figure 8A show that exocytosis- prone lysosomes, which reside near the surface of CF7 cells (Medina et al., 2011), received ATP7B H1069Q . This coincided with a stronger immunogold labeling of the mutant protein at the surface of CF7 cells compared to the parental HeLa line (Figures 8B, arrowheads, and 8C). Correspondingly, a bio- tinylation assay revealed a significant increase in the amount of ATP7B H1069Q at the surface of CF7 cells ( Figure 8D). Therefore, activation of lysosomal exocytosis allowed recovery of addi- tional quantities of ATP7B H1069Q at the cell ...
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... of Lysosomal Exocytosis Accelerates Cell Surface Delivery of the Most Frequent Wilson-Disease- Causing ATP7B Mutant Finally, we determined whether activation of lysosomal exocy- tosis could be utilized as a therapeutic strategy to contrast Wilson disease (WD) pathogenesis. The most frequent ATP7B mutant H1069Q (up to 50% in Caucasian population; Payne et al., 1998), exhibits residual catalytic activity (van den Berghe et al., 2009) but is retained within the endoplasmic reticulum (ER), where it undergoes degradation (Payne et al., 1998; van (legend continued on next page) Developmental Cell ATP7B-Driven Lysosome Exocytosis in Cu Homeostasis den Berghe et al., 2009). Thus, correction of this mutant to the regular functional compartment might be beneficial for the large cohort of the WD patients. Interestingly, despite extensive re- tention within the ER (Figures 8A and 8B, arrows), some ATP7B H1069Q gets transported to the Golgi (empty arrows in Fig- ures 8A and 8B) and further to LAMP1-positive structures (Fig- ure 8A, solid arrows). Thus, we reasoned that acceleration of lysosomal exocytosis might allow a more-efficient supply of re- sidual ATP7B H1069Q to the cell surface, where it can transport Cu out of the cell. To test this, TFEB-overexpressing CF7 cells were infected with an adenovirus carrying ATP7B H1069Q and exposed to CuSO 4 . Arrows in Figure 8A show that exocytosis- prone lysosomes, which reside near the surface of CF7 cells (Medina et al., 2011), received ATP7B H1069Q . This coincided with a stronger immunogold labeling of the mutant protein at the surface of CF7 cells compared to the parental HeLa line (Figures 8B, arrowheads, and 8C). Correspondingly, a bio- tinylation assay revealed a significant increase in the amount of ATP7B H1069Q at the surface of CF7 cells ( Figure 8D). Therefore, activation of lysosomal exocytosis allowed recovery of addi- tional quantities of ATP7B H1069Q at the cell ...
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... of Lysosomal Exocytosis Accelerates Cell Surface Delivery of the Most Frequent Wilson-Disease- Causing ATP7B Mutant Finally, we determined whether activation of lysosomal exocy- tosis could be utilized as a therapeutic strategy to contrast Wilson disease (WD) pathogenesis. The most frequent ATP7B mutant H1069Q (up to 50% in Caucasian population; Payne et al., 1998), exhibits residual catalytic activity (van den Berghe et al., 2009) but is retained within the endoplasmic reticulum (ER), where it undergoes degradation (Payne et al., 1998; van (legend continued on next page) Developmental Cell ATP7B-Driven Lysosome Exocytosis in Cu Homeostasis den Berghe et al., 2009). Thus, correction of this mutant to the regular functional compartment might be beneficial for the large cohort of the WD patients. Interestingly, despite extensive re- tention within the ER (Figures 8A and 8B, arrows), some ATP7B H1069Q gets transported to the Golgi (empty arrows in Fig- ures 8A and 8B) and further to LAMP1-positive structures (Fig- ure 8A, solid arrows). Thus, we reasoned that acceleration of lysosomal exocytosis might allow a more-efficient supply of re- sidual ATP7B H1069Q to the cell surface, where it can transport Cu out of the cell. To test this, TFEB-overexpressing CF7 cells were infected with an adenovirus carrying ATP7B H1069Q and exposed to CuSO 4 . Arrows in Figure 8A show that exocytosis- prone lysosomes, which reside near the surface of CF7 cells (Medina et al., 2011), received ATP7B H1069Q . This coincided with a stronger immunogold labeling of the mutant protein at the surface of CF7 cells compared to the parental HeLa line (Figures 8B, arrowheads, and 8C). Correspondingly, a bio- tinylation assay revealed a significant increase in the amount of ATP7B H1069Q at the surface of CF7 cells ( Figure 8D). Therefore, activation of lysosomal exocytosis allowed recovery of addi- tional quantities of ATP7B H1069Q at the cell ...
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... of Lysosomal Exocytosis Accelerates Cell Surface Delivery of the Most Frequent Wilson-Disease- Causing ATP7B Mutant Finally, we determined whether activation of lysosomal exocy- tosis could be utilized as a therapeutic strategy to contrast Wilson disease (WD) pathogenesis. The most frequent ATP7B mutant H1069Q (up to 50% in Caucasian population; Payne et al., 1998), exhibits residual catalytic activity (van den Berghe et al., 2009) but is retained within the endoplasmic reticulum (ER), where it undergoes degradation (Payne et al., 1998; van (legend continued on next page) Developmental Cell ATP7B-Driven Lysosome Exocytosis in Cu Homeostasis den Berghe et al., 2009). Thus, correction of this mutant to the regular functional compartment might be beneficial for the large cohort of the WD patients. Interestingly, despite extensive re- tention within the ER (Figures 8A and 8B, arrows), some ATP7B H1069Q gets transported to the Golgi (empty arrows in Fig- ures 8A and 8B) and further to LAMP1-positive structures (Fig- ure 8A, solid arrows). Thus, we reasoned that acceleration of lysosomal exocytosis might allow a more-efficient supply of re- sidual ATP7B H1069Q to the cell surface, where it can transport Cu out of the cell. To test this, TFEB-overexpressing CF7 cells were infected with an adenovirus carrying ATP7B H1069Q and exposed to CuSO 4 . Arrows in Figure 8A show that exocytosis- prone lysosomes, which reside near the surface of CF7 cells (Medina et al., 2011), received ATP7B H1069Q . This coincided with a stronger immunogold labeling of the mutant protein at the surface of CF7 cells compared to the parental HeLa line (Figures 8B, arrowheads, and 8C). Correspondingly, a bio- tinylation assay revealed a significant increase in the amount of ATP7B H1069Q at the surface of CF7 cells ( Figure 8D). Therefore, activation of lysosomal exocytosis allowed recovery of addi- tional quantities of ATP7B H1069Q at the cell ...
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... of Lysosomal Exocytosis Accelerates Cell Surface Delivery of the Most Frequent Wilson-Disease- Causing ATP7B Mutant Finally, we determined whether activation of lysosomal exocy- tosis could be utilized as a therapeutic strategy to contrast Wilson disease (WD) pathogenesis. The most frequent ATP7B mutant H1069Q (up to 50% in Caucasian population; Payne et al., 1998), exhibits residual catalytic activity (van den Berghe et al., 2009) but is retained within the endoplasmic reticulum (ER), where it undergoes degradation (Payne et al., 1998; van (legend continued on next page) Developmental Cell ATP7B-Driven Lysosome Exocytosis in Cu Homeostasis den Berghe et al., 2009). Thus, correction of this mutant to the regular functional compartment might be beneficial for the large cohort of the WD patients. Interestingly, despite extensive re- tention within the ER (Figures 8A and 8B, arrows), some ATP7B H1069Q gets transported to the Golgi (empty arrows in Fig- ures 8A and 8B) and further to LAMP1-positive structures (Fig- ure 8A, solid arrows). Thus, we reasoned that acceleration of lysosomal exocytosis might allow a more-efficient supply of re- sidual ATP7B H1069Q to the cell surface, where it can transport Cu out of the cell. To test this, TFEB-overexpressing CF7 cells were infected with an adenovirus carrying ATP7B H1069Q and exposed to CuSO 4 . Arrows in Figure 8A show that exocytosis- prone lysosomes, which reside near the surface of CF7 cells (Medina et al., 2011), received ATP7B H1069Q . This coincided with a stronger immunogold labeling of the mutant protein at the surface of CF7 cells compared to the parental HeLa line (Figures 8B, arrowheads, and 8C). Correspondingly, a bio- tinylation assay revealed a significant increase in the amount of ATP7B H1069Q at the surface of CF7 cells ( Figure 8D). Therefore, activation of lysosomal exocytosis allowed recovery of addi- tional quantities of ATP7B H1069Q at the cell ...
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... verify this conclusion in a liver-relevant system, polarized HepG2 cells expressing ATP7B H1069Q were infected with HDAd-TFEB and exposed to CuSO 4 for 8 hr. Confocal micro- scopy revealed that, in control cells, ATP7B H1069Q was hardly detectable within the MRP2-positive canalicular cysts, whereas overexpression of TFEB stimulated delivery of the mutant ATP7B toward the canalicular domain of hepatocytes ( Figure 8E, arrows). Therefore, activation of lysosomal exocytosis allows re- covery of additional amounts of ATP7B H1069Q at the cell ...
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The copper-transporting ATPase ATP7A contains eight transmembrane domains and is required for normal human copper homeostasis. Mutations in the ATP7A gene may lead to infantile-onset cerebral degeneration (Menkes disease); occipital horn syndrome (OHS), a related but much milder illness; or an adult-onset isolated distal motor neuropathy. The ATP7A...
Citations
... Extracellular Cu 2+ is reduced to Cu + by binding to metal reductases of the STEAP family and is transported into cells via SLC31A1 or combined with Cu 2+ chaperone protein antioxidant-1 (ATOX1) to the Golgi network via ATP7A/B (164, 165). Within the cytoplasm, excess Cu 2+ is excreted via ATP7A/B and transferred from the Golgi apparatus to other organelles to mediate cellular copper homeostasis (56). CCS1 delivers Cu 2+ to superoxide dismutase 1 (SOD1) in the cytoplasm (57,166). ...
Metal ions play an essential role in regulating the functions of immune cells by transmitting intracellular and extracellular signals in tumor microenvironment (TME). Among these immune cells, we focused on the impact of metal ions on T cells because they can recognize and kill cancer cells and play an important role in immune-based cancer treatment. Metal ions are often used in nanomedicines for tumor immunotherapy. In this review, we discuss seven metal ions related to anti-tumor immunity, elucidate their roles in immunotherapy, and provide novel insights into tumor immunotherapy and clinical applications.
... In hepatocytes, ATP7B plays a pivotal role in regulating Cu homeostasis 42 . Biallelic mutations in the ATP7B gene are known to cause Wilson's disease, which is characterized by accumulation of intracellular Cu and manifestation of liver symptoms such as acute hepatitis, hepatomegaly, jaundice, and cirrhosis 43 . ...
Anti-tuberculosis (AT) medications, including isoniazid (INH), can cause drug-induced liver injury (DILI), but the underlying mechanism remains unclear. In this study, we aimed to identify genetic factors that may increase the susceptibility of individuals to AT-DILI and to examine genetic interactions that may lead to isoniazid (INH)-induced hepatotoxicity. We performed a targeted sequencing analysis of 380 pharmacogenes in a discovery cohort of 112 patients (35 AT-DILI patients and 77 controls) receiving AT treatment for active tuberculosis. Pharmacogenome-wide association analysis was also conducted using 1048 population controls (Korea1K). NAT2 and ATP7B genotypes were analyzed in a replication cohort of 165 patients (37 AT-DILI patients and 128 controls) to validate the effects of both risk genotypes. NAT2 ultraslow acetylators (UAs) were found to have a greater risk of AT-DILI than other genotypes (odds ratio [OR] 5.6 [95% confidence interval; 2.5–13.2], P = 7.2 × 10−6). The presence of ATP7B gene 832R/R homozygosity (rs1061472) was found to co-occur with NAT2 UA in AT-DILI patients (P = 0.017) and to amplify the risk in NAT2 UA (OR 32.5 [4.5–1423], P = 7.5 × 10−6). In vitro experiments using human liver-derived cell lines (HepG2 and SNU387 cells) revealed toxic synergism between INH and Cu, which were strongly augmented in cells with defective NAT2 and ATP7B activity, leading to increased mitochondrial reactive oxygen species generation, mitochondrial dysfunction, DNA damage, and apoptosis. These findings link the co-occurrence of ATP7B and NAT2 genotypes to the risk of INH-induced hepatotoxicity, providing novel mechanistic insight into individual AT-DILI susceptibility.
... The latter is a copper exporter and is recognized for having undergone alteration in Wilson's disease, where its loss of activity leads to a malfunction to eliminate enough copper, producing toxic copper deposition in a number of tissues, particularly the brain and liver [122]. In response to copper exposure, it has recently been demonstrated that ATP7B moves from the Golgi apparatus to the lysosomes, where it promotes lysosomal copper build up and lysosomal exocytosis, leading to copper clearance from the cell [123,124]. In KB-3-1 cervical cancer cells, overexpression of ATP7B decreased cisplatin accumulation and, as a result, cisplatin resistance [125]. ...
Chemotherapy is still the major method of treatment for many types of cancer. Curative cancer therapy is hampered significantly by medication resistance. Acidic organelles like lysosomes serve as protagonists in cellular digestion. Lysosomes, however, are gaining popularity due to their speeding involvement in cancer progression and resistance. For instance, weak chemotherapeutic
drugs of basic nature permeate through the lysosomal membrane and are retained in lysosomes in their cationic state, while extracellular release of lysosomal enzymes induces cancer, cytosolic escape of lysosomal hydrolases causes apoptosis, and so on. Drug availability at the sites of action is decreased due to lysosomal drug sequestration, which also enhances cancer resistance. This review looks at lysosomal drug sequestration mechanisms and how they affect cancer treatment resistance.
Using lysosomes as subcellular targets to combat drug resistance and reverse drug sequestration is another method for overcoming drug resistance that is covered in this article. The present review has identified lysosomal drug sequestration as one of the reasons behind chemoresistance. The article delves deeper into specific aspects of lysosomal sequestration, providing nuanced insights, critical evaluations, or novel interpretations of different approaches that target lysosomes to defect cancer.
... 4 In response to elevated Cu, ATP7B traffics from the TGN to endo-lysosomal organelles where it drives sequestration of excess Cu and promotes its further biliary excretion via lysosomal exocytosis. 5 Loss of ATP7B function impairs biliary Cu excretion and Cu incorporation in ceruloplasmin. This leads to hepatic Cu overload, with subsequent damage of hepatic cells and accumulation of Cu in other organs including the brain, kidney, and eye. ...
... A growing body of evidence suggests that the H1069Q mutant of ATP7B undergoes significant retention and degradation in the ER. 5,11,12,29 This does not allow newly synthetized ATP7B-H1069Q ...
... For this purpose, animals expressing the GFP-tagged version of the mutant protein were treated with the proteasome inhibitor MG132, which has been shown to suppress ER degradation of ATP7B-H1069Q. 5,20 We observed that in animals expressing low CUA-1 H828Q levels, the mutant protein was hardly detectable in the ER and resided mainly at the cell membrane ( Figure 7C, F, G) while MG132-treated animals exhibited a detectable GFP-CUA-1 H828Q signal in the ER regardless of the expression level ( Figure 7E, H, I). Thus, ER accumulation of CUA-1 H828Q upon MG132 treatment suggests that a significant amount of the ER-retained mutant protein undergoes degradation. ...
Wilson disease (WD) is caused by mutations in the ATP7B gene that encodes a copper (Cu) transporting ATPase whose trafficking from the Golgi to endo‐lysosomal compartments drives sequestration of excess Cu and its further excretion from hepatocytes into the bile. Loss of ATP7B function leads to toxic Cu overload in the liver and subsequently in the brain, causing fatal hepatic and neurological abnormalities. The limitations of existing WD therapies call for the development of new therapeutic approaches, which require an amenable animal model system for screening and validation of drugs and molecular targets. To achieve this objective, we generated a mutant Caenorhabditis elegans strain with a substitution of a conserved histidine (H828Q) in the ATP7B ortholog cua‐1 corresponding to the most common ATP7B variant (H1069Q) that causes WD. cua‐1 mutant animals exhibited very poor resistance to Cu compared to the wild‐type strain. This manifested in a strong delay in larval development, a shorter lifespan, impaired motility, oxidative stress pathway activation, and mitochondrial damage. In addition, morphological analysis revealed several neuronal abnormalities in cua‐1 mutant animals exposed to Cu. Further investigation suggested that mutant CUA‐1 is retained and degraded in the endoplasmic reticulum, similarly to human ATP7B‐H1069Q. As a consequence, the mutant protein does not allow animals to counteract Cu toxicity. Notably, pharmacological correctors of ATP7B‐H1069Q reduced Cu toxicity in cua‐1 mutants indicating that similar pathogenic molecular pathways might be activated by the H/Q substitution and, therefore, targeted for rescue of ATP7B/CUA‐1 function. Taken together, our findings suggest that the newly generated cua‐1 mutant strain represents an excellent model for Cu toxicity studies in WD.
... 28 Elevated copper also triggers lysosomal exocytosis, and thus, excess copper is excreted out. 6,7,29 In this study, we have demonstrated that a significant fraction of the total ATP7B pool is present on the endolysosomal compartment irrespective of cellular copper concentration, and this localisation of ATP7B is exclusively hepatocyte-specific. We further observed a pool of lysosomes apposing close to the TGN that harbours this fraction of ATP7B in basal or copper-chelated conditions. ...
... It is well-documented that ATP7B is directly transported to the endolysosomal compartment (late secretory pathway) and not by the endocytic pathway of lysosomal maturation via the plasma membrane. 6 To circumvent copper-induced toxicity, this type of direct transport ensures faster response in elevated copper conditions. A recent study has shown that TGN-associated lysosome acts as a hub for secretory, endosomal, and autophagic routes in drosophila. ...
... In addition, we also observed a slight increase in lysotracker intensity labelling the lysosomes in flow cytometry analysis of cells in copper-treated condition ( Figure 6L,M). We also observed an increase in lysosomal exocytosis upon copper treatment as determined by hexosaminidase activity ( Figure 6N), which corroborates with previous findings by Polishchuk et al. 6 To summarise, increasing the abundance of perinuclear lysosomes augments endolysosomal localisation of ATP7B that happens via the exchange of the protein between the TGN and its proximal lysosomes F I G U R E 6 Legend on next page. ...
In hepatocytes, the Wilson disease protein ATP7B resides on the trans ‐Golgi network (TGN) and traffics to peripheral lysosomes to export excess intracellular copper through lysosomal exocytosis. We found that in basal copper or even upon copper chelation, a significant amount of ATP7B persists in the endolysosomal compartment of hepatocytes but not in non‐hepatic cells. These ATP7B‐harbouring lysosomes lie in close proximity of ~10 nm to the TGN. ATP7B constitutively distributes itself between the sub‐domain of the TGN with a lower pH and the TGN‐proximal lysosomal compartments. The presence of ATP7B on TGN‐lysosome colocalising sites upon Golgi disruption suggested a possible exchange of ATP7B directly between the TGN and its proximal lysosomes. Manipulating lysosomal positioning significantly alters the localisation of ATP7B in the cell. Contrary to previous understanding, we found that upon copper chelation in a copper‐replete hepatocyte, ATP7B is not retrieved back to TGN from peripheral lysosomes; rather, ATP7B recycles to these TGN‐proximal lysosomes to initiate the next cycle of copper transport. We report a hitherto unknown copper‐independent lysosomal localisation of ATP7B and the importance of TGN‐proximal lysosomes but not TGN as the terminal acceptor organelle of ATP7B in its retrograde pathway.
... In the context of increased copper, ATP7A/B are transported from the Golgi to post-Golgi or lysosomes, thus promoting the efflux of excessive copper. 43 Mediator of cell motility 1 (MEMO1) binds Cu + and interacts with ATOX1, and prevents copper-mediated redox activity. 44 Cisplatin binds to ATOX1 regardless of whether copper exists; however, it is unstable over time and the protein starts to unfold and aggregate. ...
Copper is an essential nutrient for maintaining enzyme activity and transcription factor function. Excess copper results in the aggregation of lipoylated dihydrolipoamide S‐acetyltransferase (DLAT), which correlates to the mitochondrial tricarboxylic acid (TCA) cycle, resulting in proteotoxic stress and eliciting a novel cell death modality: cuproptosis. Cuproptosis exerts an indispensable role in cancer progression, which is considered a promising strategy for cancer therapy. Cancer immunotherapy has gained extensive attention owing to breakthroughs in immune checkpoint blockade; furthermore, cuproptosis is strongly connected to the modulation of antitumor immunity. Thus, a thorough recognition concerning the mechanisms involved in the modulation of copper metabolism and cuproptosis may facilitate improvement in cancer management. This review outlines the cellular and molecular mechanisms and characteristics of cuproptosis and the links of the novel regulated cell death modality with human cancers. We also review the current knowledge on the complex effects of cuproptosis on antitumor immunity and immune response. Furthermore, potential agents that elicit cuproptosis pathways are summarized. Lastly, we discuss the influence of cuproptosis induction on the tumor microenvironment as well as the challenges of adding cuproptosis regulators to therapeutic strategies beyond traditional therapy.
... Polishchuk et al. analyzed gene enrichment using the ATP7B mouse model and found that an insufficient level of ATP7B restricted Cu efflux and increased intracellular Cu concentration [88]. The autophagy marker MAP1LC3 (also known as LC3) level was greatly increased, indicating that autophagy was activated while also interfering with the inactivation of the mammalian target of rapamycin (mTOR)dependent signaling on the lysosomal membrane [89,90]. Autophagy is still promoted by mTOR deactivation because it can stimulate dephosphorylation and transcription factor EB (TFEB) translocation to the nucleus [88,91]. ...
... (mTOR)-dependent signaling on the lysosomal membrane [89,90]. Autophagy is still pro moted by mTOR deactivation because it can stimulate dephosphorylation and transcrip tion factor EB (TFEB) translocation to the nucleus [88,91]. ...
Nanotechnology, an emerging and promising therapeutic tool, may improve the effectiveness of phototherapy (PT) in antitumor therapy because of the development of nanomaterials (NMs) with light-absorbing properties. The tumor-targeted PTs, such as photothermal therapy (PTT) and photodynamic therapy (PDT), transform light energy into heat and produce reactive oxygen species (ROS) that accumulate at the tumor site. The increase in ROS levels induces oxidative stress (OS) during carcinogenesis and disease development. Because of the localized surface plasmon resonance (LSPR) feature of copper (Cu), a vital trace element in the human body, Cu-based NMs can exhibit good near-infrared (NIR) absorption and excellent photothermal properties. In the tumor microenvironment (TME), Cu2+ combines with H2O2 to produce O2 that is reduced to Cu1+ by glutathione (GSH), causing a Fenton-like reaction that reduces tumor hypoxia and simultaneously generates ROS to eliminate tumor cells in conjunction with PTT/PDT. Compared with other therapeutic modalities, PTT/PDT can precisely target tumor location to kill tumor cells. Moreover, multiple treatment modalities can be combined with PTT/PDT to treat a tumor using Cu-based NMs. Herein, we reviewed and briefly summarized the mechanisms of actions of tumor-targeted PTT/PDT and the role of Cu, generated from Cu-based NMs, in PTs. Furthermore, we described the Cu-based NMs used in PTT/PDT applications.
... Upon excess copper levels, hepatic ATP7B translocates from the Golgi apparatus to the lysosome and moves copper to its lumen (Petruzzelli et al., 2022). Then, ATP7B promotes exocytosis mediated by p62, importing excess copper into the bile and subsequently exiled out for the body (Polishchuk et al., 2014). The gastrointestinal tract can also influence the direct transport of copper by hepatic ATP7B on the apical membrane. ...
Copper (Cu) is a vital trace element for maintaining human health. Current evidence suggests that genes responsible for regulating copper influx and detoxification help preserve its homeostasis. Adequate Cu levels sustain normal cardiac and blood vessel activity by maintaining mitochondrial function. Cuproptosis, unlike other forms of cell death, is characterized by alterations in mitochondrial enzymes. Therapeutics targeting cuproptosis in cardiovascular diseases (CVDs) mainly include copper chelators, inhibitors of copper chaperone proteins, and copper ionophores. In this review, we expound on the primary mechanisms, critical proteins, and signaling pathways involved in cuproptosis, along with its impact on CVDs and the role it plays in different types of cells. Additionally, we explored the influence of key regulatory proteins and signaling pathways associated with cuproptosis on CVDs and determined whether intervening in copper metabolism and cuproptosis can enhance the outcomes of CVDs. The insights from this review provide a fresh perspective on the pathogenesis of CVDs and new targets for intervention in these diseases.
... Current treatments for WD include limiting dietary copper intake, using zinc to reduce copper absorption, copper chelation to remove copper from tissues, and symptomatic treatment. Polishchuk et al. [36] found that activating lysosomal exocytosis stimulated hepatocytes to clear copper and relocated the most common pathogenic ATP7B mutant back to its appropriate functional site. Therefore, targeting ATP7B-dependent lysosomal exocytosis may be a promising therapeutic strategy for use in patients with WD. ...
Copper (Cuprum) is an essential trace metal indispensable for the function of numerous enzymatic molecules implicated in cellular metabolism. Emerging evidence has demonstrated the role of copper in angiogenesis and cellular signaling. Moreover, raised copper levels have been detected in hepatocellular carcinoma and other cancers. An inherited or acquired copper imbalance, including inadequately low or excessively high copper levels, as well as inappropriate copper distribution in the body, is implicated in a number of diseases. In addition, a recent groundbreaking study identified a copper‐induced type of programmed cell death named cuprotosis, the mechanism of which greatly deferred from that of other known cell death modes. The first part provides an overview of the regulation of copper homeostasis and discusses the underlying mechanisms of cuprotosis. In the second part, the authors focus on the functions of copper in liver diseases and other metabolic disorders, before discussing how this knowledge could contribute to the development of effective targets to treat such diseases.
... The distribution of ATR1 in cells is dynamic, elevation of extracellular copper induces endocytosis of CTR1 to vesicles, whereas a decrease in extracellular cooper restores CTR1 (Lutsenko, 2010). Excessive copper is excreted into bile in the form of vesicles by ATP7B, while ATP7A can mobilize copper from liver storage to maintain effective copper concentration (Polishchuk Elena et al., 2014). Copper deficiency can lead to oxidative stress and cytotoxicity, while copper excess can also be toxic. ...
Copper is an essential micronutrient that plays a critical role in many physiological processes. However, excessive copper accumulation in cancer cells has been linked to tumor growth and metastasis. This review article explores the potential of targeting copper metabolism as a promising strategy for cancer treatment. Excessive copper accumulation in cancer cells has been associated with tumor growth and metastasis. By disrupting copper homeostasis in cancer cells and inducing cell death through copper-dependent mechanisms (cuproplasia and cuprotosis, respectively), therapies can be developed with improved efficacy and reduced side effects. The article discusses the role of copper in biological processes, such as angiogenesis, immune response, and redox homeostasis. Various approaches for targeting copper metabolism in cancer treatment are examined, including the use of copper-dependent enzymes, copper-based compounds, and cuprotosis-related genes or proteins. The review also explores strategies like copper chelation therapy and nanotechnology for targeted delivery of copper-targeting agents. By understanding the intricate network of cuprotosis and its interactions with the tumor microenvironment and immune system, new targets for therapy can be identified, leading to improved cancer treatment outcomes. Overall, this comprehensive review highlights the significant potential of targeting copper metabolism as a promising and effective approach in cancer treatment, while providing valuable insights into the current state of research in this field.
