Non-hepatic tumors change the activity of genes encoding copper trafficking proteins in the liver

Babich, Polina S.; Skvortsov, A. N.; Rusconi, Paolo; Tsymbalenko, N. V.; Mutanen, Marja; Puchkova, L. V.; Broggini, Massimo

doi:10.4161/cbt.24594

Cited by 17 publications

(17 citation statements)

References 52 publications

(48 reference statements)

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“…Indeed, it was recently shown that an Ag diet can be successfully used for this purpose [98]. One of the general signs of tumor development, regardless of its nature, is increased copper consumption, which is manifested in the activation of copper metabolism genes [164]. In this context, Ag(I) might interfere with cuproenzyme synthesis and angiogenesis, which both require copper to promote tumor growth.…”

Section: Interplay Between Silver and Pathways Driving Intracellulmentioning

confidence: 99%

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Silver Ions as a Tool for Understanding Different Aspects of Copper Metabolism

et al. 2019

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In humans, copper is an important micronutrient because it is a cofactor of ubiquitous and brain-specific cuproenzymes, as well as a secondary messenger. Failure of the mechanisms supporting copper balance leads to the development of neurodegenerative, oncological, and other severe disorders, whose treatment requires a detailed understanding of copper metabolism. In the body, bioavailable copper exists in two stable oxidation states, Cu(I) and Cu(II), both of which are highly toxic. The toxicity of copper ions is usually overcome by coordinating them with a wide range of ligands. These include the active cuproenzyme centers, copper-binding protein motifs to ensure the safe delivery of copper to its physiological location, and participants in the Cu(I) ↔ Cu(II) redox cycle, in which cellular copper is stored. The use of modern experimental approaches has allowed the overall picture of copper turnover in the cells and the organism to be clarified. However, many aspects of this process remain poorly understood. Some of them can be found out using abiogenic silver ions (Ag(I)), which are isoelectronic to Cu(I). This review covers the physicochemical principles of the ability of Ag(I) to substitute for copper ions in transport proteins and cuproenzyme active sites, the effectiveness of using Ag(I) to study copper routes in the cells and the body, and the limitations associated with Ag(I) remaining stable in only one oxidation state. The use of Ag(I) to restrict copper transport to tumors and the consequences of large-scale use of silver nanoparticles for human health are also discussed.

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Section: Interplay Between Silver and Pathways Driving Intracellulmentioning

confidence: 99%

“…In this context, Ag(I) might interfere with cuproenzyme synthesis and angiogenesis, which both require copper to promote tumor growth. In line with this notion, a diet including Ag was shown to inhibit the growth of human tumors engrafted into nude mice [164].…”

Section: Interplay Between Silver and Pathways Driving Intracellulmentioning

confidence: 99%

Silver Ions as a Tool for Understanding Different Aspects of Copper Metabolism

et al. 2019

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“…In ( Figure 5C). Moreover, in all KO clones, ceruloplasmin was detected as two bands that correspond to holo-and apo-ceruloplasmin [24]. Peer-reviewed version available at Cells 2019, 8, 322; doi:10.3390/cells8040322 of In DMT1-KO cells, the expression of the HIF1, COMMD1, XIAP, and CCS genes is reduced by more than 2 times while NF-kB and SOD1 levels were almost unchanged.…”

Section: Resultsmentioning

confidence: 96%

CRISP-R/Cas9 Mediated Deletion of Copper Transport Genes CTR1 and DMT1 in NSCLC Cell Line H1299. Biological and Pharmacological Consequences

Ilyechova

Bonaldi

Orlov

et al. 2018

Preprint

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Copper, the highly toxicity micronutrient, plays two essential roles: it is a catalytic and structural cofactor for Cu-dependent enzymes, and it acts as a secondary messenger. In the cells, copper is imported by CTR1, a transmembrane high-affinity copper importer, and DMT1 (divalent metal transporter). In cytosol, enzyme-specific chaperones receive copper from CTR1 C-terminus and deliver it to their apoenzymes. DMT1 cannot be a donor of catalytic copper because it does not have cytosol domain which is required for copper transfer to the Cu-chaperons and following to cuproenzymes. Here we assume that DMT1 can mediate copper way required for regulatory copper pool. To verify this thought, we used CRISPR/Cas9 to generate H1299 cell line with CTR1 or DMT1 single knockout (KO) and CTR1/DMT1 double knockout (DKO). To confirm KOs of the genes qRT-PCR were used. Two independent clones for each gene were selected for further studies. In CTR1-KO cells, expression of the DMT1 gene was significantly increased. In subcellular compartments, copper concentration decreased dramatically in DKO cells. CTR1-KO cells, but not DMT1-KO, demonstrated reduced sensitivity to cisplatin and silver ions, agents that enter the cell through CTR1. The expression of genes, whose protein products require copper: HIF1α, XIAP, COMMD1, CCS, Cp, but not SOD1 and NF-kB, changed their level. Perhaps these data will help to understand how the disturbances of copper homeodynamics lead to the development of neurodegenerative and oncological disorders. Possibility of using CTR1 KO and DMT1 KO cells to study homeodynamics of catalytic and signaling copper selectively is discussed.

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“…Ag(I) is isoelectronic to Cu(I) so it is efficiently bound by Cu(I) transporters and carriers; however, it cannot be oxidized in aqueous media, and when included instead of copper to cuproenzymes, it disrupts their structure and catalytic activity [ 28 ]. This may be a basis for the use of silver to retard the growth of tumors that require increased amounts of copper [ 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

The Extracellular Domain of Human High Affinity Copper Transporter (hNdCTR1), Synthesized by E. coli Cells, Chelates Silver and Copper Ions In Vivo

et al. 2017

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There is much interest in effective copper chelators to correct copper dyshomeostasis in neurodegenerative and oncological diseases. In this study, a recombinant fusion protein for expression in Escherichia coli cells was constructed from glutathione-S-transferase (GST) and the N-terminal domain (ectodomain) of human high affinity copper transporter CTR1 (hNdCTR1), which has three metal-bound motifs. Several biological properties of the GST-hNdCTR1 fusion protein were assessed. It was demonstrated that in cells, the protein was prone to oligomerization, formed inclusion bodies and displayed no toxicity. Treatment of E. coli cells with copper and silver ions reduced cell viability in a dose- and time-dependent manner. Cells expressing GST-hNdCTR1 protein demonstrated resistance to the metal treatments. These cells accumulated silver ions and formed nanoparticles that contained AgCl and metallic silver. In this bacterial population, filamentous bacteria with a length of about 10 µm were often observed. The possibility for the fusion protein carrying extracellular metal binding motifs to integrate into the cell’s copper metabolism and its chelating properties are discussed.

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Non-hepatic tumors change the activity of genes encoding copper trafficking proteins in the liver

Cited by 17 publications

References 52 publications

Silver Ions as a Tool for Understanding Different Aspects of Copper Metabolism

Silver Ions as a Tool for Understanding Different Aspects of Copper Metabolism

CRISP-R/Cas9 Mediated Deletion of Copper Transport Genes CTR1 and DMT1 in NSCLC Cell Line H1299. Biological and Pharmacological Consequences

The Extracellular Domain of Human High Affinity Copper Transporter (hNdCTR1), Synthesized by E. coli Cells, Chelates Silver and Copper Ions In Vivo

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