Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion

Cancer Research, Journal Year: 2020, Volume and Issue: 80(19), P. 4129 - 4144

Published: Aug. 18, 2020

Abstract Therapeutic checkpoint antibodies blocking programmed death receptor 1/programmed ligand 1 (PD-L1) signaling have radically improved clinical outcomes in cancer. However, the regulation of PD-L1 expression on tumor cells is still poorly understood. Here we show that intratumoral copper levels influence cancer cells. Deep analysis The Cancer Genome Atlas database and tissue microarrays showed strong correlation between major influx transporter (CTR-1) across many cancers but not corresponding normal tissues. Copper supplementation enhanced at mRNA protein RNA sequencing revealed regulates key pathways mediating PD-L1–driven immune evasion. Conversely, chelators inhibited phosphorylation STAT3 EGFR promoted ubiquitin-mediated degradation PD-L1. Copper-chelating drugs also significantly increased number tumor-infiltrating CD8+ T natural killer cells, slowed growth, mouse survival. Overall, this study reveals an important role for regulating suggests anticancer immunotherapy might be by pharmacologically reducing intratumor levels. Significance: These findings characterize modulating contributing to evasion, highlighting potential repurposing as enhancers antitumor immunity.

Language: Английский

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A lytic polysaccharide monooxygenase-like protein functions in fungal copper import and meningitis

Nature Chemical Biology, Journal Year: 2020, Volume and Issue: 16(3), P. 337 - 344

Published: Jan. 13, 2020

Language: Английский

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Extracellular Cu2+ pools and their detection: From current knowledge to next-generation probes

Coordination Chemistry Reviews, Journal Year: 2021, Volume and Issue: 433, P. 213727 - 213727

Published: Feb. 8, 2021

Language: Английский

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Redox-Active Metal Ions and Amyloid-Degrading Enzymes in Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(14), P. 7697 - 7697

Published: July 19, 2021

Redox-active metal ions, Cu(I/II) and Fe(II/III), are essential biological molecules for the normal functioning of brain, including oxidative metabolism, synaptic plasticity, myelination, generation neurotransmitters. Dyshomeostasis these redox-active ions in brain could cause Alzheimer’s disease (AD). Thus, regulating levels Fe(II/III) is necessary function. To control amounts understand involvement pathogenesis AD, many chemical agents have been developed. In addition, since toxic aggregates amyloid-β (Aβ) proposed as one major causes disease, mechanism clearing Aβ also required to be investigated reveal etiology AD clearly. Multiple metalloenzymes (e.g., neprilysin, insulin-degrading enzyme, ADAM10) reported an important role degradation brain. These amyloid degrading enzymes (ADE) interact with affect AD. this review, we introduce summarize roles, distributions, transportations along previously invented chelators, structures functions ADE well their interrelationships.

Language: Английский

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The Sub‐picomolar Cu²⁺ Dissociation Constant of Human Serum Albumin

ChemBioChem, Journal Year: 2019, Volume and Issue: 21(3), P. 331 - 334

Published: July 12, 2019

The apparent affinity of human serum albumin (HSA) for divalent copper has long been the subject great interest, due to its presumed role as major Cu2+ -binding ligand in blood and cerebrospinal fluid. Using a combination electronic absorption, circular dichroism room-temperature electron paramagnetic resonance spectroscopies, together with potentiometric titrations, we competed tripeptide GGH against HSA reveal conditional binding constant log cKCuCu(HSA) =13.02±0.05 at pH 7.4. This rigorously determined value important implications understanding extracellular distribution copper.

Language: Английский

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Key Intermediate Species Reveal the Copper(II)‐Exchange Pathway in Biorelevant ATCUN/NTS Complexes

Angewandte Chemie International Edition, Journal Year: 2020, Volume and Issue: 59(28), P. 11234 - 11239

Published: April 8, 2020

Abstract The amino‐terminal copper and nickel/N‐terminal site (ATCUN/NTS) present in proteins bioactive peptides exhibits high affinity towards Cu II ions have been implicated human physiology. Little is known, however, about the rate exact mechanism of formation such complexes. We used stopped‐flow microsecond freeze‐hyperquenching (MHQ) techniques supported by steady‐state spectroscopic electrochemical data to demonstrate partially coordinated intermediate complexes formed glycyl–glycyl–histidine (GGH) peptide, simplest ATCUN/NTS model. One these novel intermediates, characterized two‐nitrogen coordination, t 1/2 ≈100 ms at pH 6.0 ability maintain /Cu I redox pair best candidate for long‐sought reactive species extracellular transport.

Language: Английский

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Copper Sources for Sod1 Activation

Antioxidants, Journal Year: 2020, Volume and Issue: 9(6), P. 500 - 500

Published: June 7, 2020

Copper ions (i.e., copper) are a critical part of several cellular processes, but tight regulation copper levels and trafficking required to keep the cell protected from this highly reactive transition metal. Cu, Zn superoxide dismutase (Sod1) protects accumulation radical oxygen species by way redox cycling activity in its catalytic center. Multiple posttranslational modification events, including incorporation, reliant on chaperone for Sod1 (Ccs). The high-affinity uptake protein (Ctr1) is main entry point into eukaryotic cells can directly supply Ccs along with other known intracellular chaperones molecules. This review explores routes delivery that utilized activate usefulness necessity each.

Language: Английский

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Copper(II) import and reduction are dependent on His-Met clusters in the extracellular amino terminus of human copper transporter-1

Journal of Biological Chemistry, Journal Year: 2022, Volume and Issue: 298(3), P. 101631 - 101631

Published: Jan. 26, 2022

Copper(I) is an essential metal for all life forms. Though Cu(II) the most abundant and stable state, its reduction to Cu(I) via unclear mechanism prerequisite bioutilization. In eukaryotes, copper transporter-1 (CTR1) primary high-affinity importer, although role in remain uncharacterized. Here we show that extracellular amino-terminus of human CTR1 contains two methionine-histidine clusters neighboring aspartates distinctly bind preceding import. We determined hCTR1 localizes at basolateral membrane polarized MDCK-II cells endocytosis Common-Recycling-Endosomes regulated by subsequent coordination methionine cluster. demonstrate transient binding both during process facilitated also act as another crucial determinant endocytosis. Mutating first Methionine cluster (7Met-Gly-Met9) Asp13 abrogated uptake upon treatment. This phenotype could be reverted treating with reduced nonreoxidizable Cu(I). histidine clusters, on other hand, are functioning limiting copper. Finally, N-terminal His-Met-Asp exhibit functional complementarity, second sufficient preserve copper-induced complete deletion propose a novel detailed which residues not only copper, but maintain intracellular uptake.

Language: Английский

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Cu^II Binding Properties of N-Truncated Aβ Peptides: In Search of Biological Function

Inorganic Chemistry, Journal Year: 2019, Volume and Issue: 58(20), P. 13561 - 13577

Published: July 15, 2019

As life expectancy increases, the number of people affected by progressive and irreversible dementia, Alzheimer's Disease (AD), is predicted to grow. No drug designs seem be working in humans, apparently because origins AD have not been identified. Invoking amyloid cascade, metal ions, ROS production hypothesis AD, herein we share our point view on Cu(II) binding properties Aβ4–x, most prevalent N-truncated Aβ peptide, currently known as main constituent plaques. The capability Aβ4–x rapidly take over copper from previously tested Aβ1–x peptides form highly stable complexes, redox unreactive resistant exchange reactions, prompted us propose physiological roles for these peptides. We discuss new findings reactivity Cu(II)Aβ4–x with coexisting biomolecules context synaptic cleft; suggest that role quench toxicity brain maintain neurotransmission.

Language: Английский

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How trimerization of CTR1 N-terminal model peptides tunes Cu-binding and redox-chemistry

Chemical Communications, Journal Year: 2020, Volume and Issue: 56(81), P. 12194 - 12197

Published: Jan. 1, 2020

Trimeric arrangement of model peptides the CTR1 N-terminus promotes Cu(ii) reduction and Cu(i) binding.

Language: Английский

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