Single-cell tracking demonstrates copper chaperone Atox1 to be required for breast cancer cell migration

Blockhuys, Stéphanie; Zhang, Xiaolu; Wittung-Stafshede, Pernilla

doi:10.1073/pnas.1910722117

Cited by 102 publications

(80 citation statements)

References 49 publications

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“…Typically, highly proliferating tumors are characterized by selective Cu accumulation in the nuclei, whereas normal tissue predominantly accumulates Cu within the cytoplasm [ 87 , 88 , 89 ]. In agreement with this observation, cancer cells are characterized by increased nuclear translocation of Atox1, which correlated with the severity of the disease; therefore, nuclear status of Atox1 might determine the proliferation status of the cells [ 90 , 91 ].…”

Section: Tumor Modulation With Inorganic Cu Saltsmentioning

confidence: 64%

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

2021

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

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Section: Tumor Modulation With Inorganic Cu Saltsmentioning

confidence: 64%

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

2021

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“…Knockdown of ATOX1 in SW620 decreased ROS generation and colony formation through a decreased expression of NADPH oxidase p47phox and Cyclin D1 ( Jana et al, 2020 ). Individual cell migration is an early step in breast cancer metastasis; thus, ATOX1 silencing decreases the breast cancer cell migration velocity via coordinated copper transport in the ATP7A-LOX (proenzyme of lysyl oxidase) axis ( Blockhuys et al, 2020 ).…”

Section: Mechanisms Of Copper Action On Tumor Developmentmentioning

confidence: 99%

Role of Copper on Mitochondrial Function and Metabolism

Ruíz

Libedinsky

Elorza

2021

Front. Mol. Biosci.

304

174

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Copper is essential for life processes like energy metabolism, reactive oxygen species detoxification, iron uptake, and signaling in eukaryotic organisms. Mitochondria gather copper for the assembly of cuproenzymes such as the respiratory complex IV, cytochrome c oxidase, and the antioxidant enzyme superoxide dismutase 1. In this regard, copper plays a role in mitochondrial function and signaling involving bioenergetics, dynamics, and mitophagy, which affect cell fate by means of metabolic reprogramming. In mammals, copper homeostasis is tightly regulated by the liver. However, cellular copper levels are tissue specific. Copper imbalances, either overload or deficiency, have been associated with many diseases, including anemia, neutropenia, and thrombocytopenia, as well as tumor development and cancer aggressivity. Consistently, new pharmacological developments have been addressed to reduce or exacerbate copper levels as potential cancer therapies. This review goes over the copper source, distribution, cellular uptake, and its role in mitochondrial function, metabolic reprograming, and cancer biology, linking copper metabolism with the field of regenerative medicine and cancer.

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“…From a tissue microarray, the increased nuclear translocation of Atox1 was observed in metastatic colorectal cancer (CRC), and was correlated with the severity of the disease [50]. The nuclear localization of Atox1 was also correlated with increased migration capabilities in breast cancer cells, in an ATP7A-and LOX-dependent mechanism [51]. Indeed, the co-localization of the three proteins, Atox1, ATP7A and LOX, was observed at the lamellipodia border of the cell.…”

Section: The Use Of Copper Proteins As Cancer Biomarkersmentioning

confidence: 99%

The Multifaceted Roles of Copper in Cancer: a Trace Metal Element with Dysregulated Metabolism, but also a Target or a Bullet for Therapy

Lelièvre

Sancey

Coll

et al. 2020

Preprint

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In the human body, Copper (Cu) is a major and essential player in a large number of cellular mechanisms and signaling pathways. The involvement of Cu in oxidation-reduction reactions requires close regulation of copper metabolism in order to avoid toxic effects. In many types of cancer, variations in copper protein levels have been demonstrated. These variations result in increased concentrations of intra-tumoral Cu and alterations in the systemic distribution of copper. Such alterations in Cu homeostasis may promote tumor growth or invasiveness, or even confer resistance to treatments. Once characterized, the dysregulated Cu metabolism is pinpointing several promising biomarkers for clinical use, with prognostic or predictive capabilities. The altered Cu metabolism in cancer cells and the different responses of tumor cells to Cu are strongly supporting the development of treatments to disrupt, deplete or increase Cu levels in tumors. The metallic nature of Cu, as a chemical element, is key for the development of anticancer agents via the synthesis of nanoparticles or copper-based complexes with antineoplastic properties for therapy. Finally, some of these new therapeutic strategies such as chelators or ionophores have shown promising results in a preclinical setting, while others are already in the clinic.

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Single-cell tracking demonstrates copper chaperone Atox1 to be required for breast cancer cell migration

Cited by 102 publications

References 49 publications

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

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

Role of Copper on Mitochondrial Function and Metabolism

The Multifaceted Roles of Copper in Cancer: a Trace Metal Element with Dysregulated Metabolism, but also a Target or a Bullet for Therapy

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