Integrated Redox Proteomic Analysis Highlights New Mechanisms of Sensitivity to Silver Nanoparticles

Holmila, Reetta; Wu, Hanzhi; Lee, Jingyun; Tsang, Allen W.; Singh, Ravi; Furdui, Cristina M.

doi:10.1016/j.mcpro.2021.100073

Cited by 15 publications

(15 citation statements)

References 64 publications

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“…Although DCP-NEt2C is specific for detection of oxidized thiols in mitochondria, we observed DCP-Net2C labeling to be correlated with other metrics of total thiol oxidation in lung cells treated with AgNPs [ 13 ]. Furthermore, we previously found that an increase in sulfenylated proteins following AgNP treatment was characteristic of AgNP sensitive breast and lung cancer cells using biotinylated, dimedone-based probes to detect protein sulfenic acids by western blot [ 9 ], and by quantification of total reversible protein thiol oxidation using mass spectrometry [ 14 ]. The second method we used here to assess proteotoxicity involved staining with proteostat after paraformaldehyde fixation for the formation of protein aggregates in AgNP-treated cells.…”

Section: Discussionmentioning

confidence: 99%

“…For example, previous studies show that some breast cancer cell lines are more sensitive to AgNP exposure than non-neoplastic mammary epithelial cells [ 9 – 11 ]. Similarly, there is substantial variability in the sensitivity of ovarian cancer [ 12 ], lung cancer [ 13 , 14 ], and leukemia cell lines [ 15 ] to AgNP exposure. Our previous recent results show that sensitivity to Ag + exposure does not correlate with sensitivity to intact AgNPs [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…After uptake, AgNPs appear to remain confined to membrane bound vesicles including early and late endosomes, and autophagosomes [ 11 ]. Despite this, AgNP-induced damage is observed in almost every part of the cell, including mitochondria [ 13 , 14 ], nucleus [ 9 ], and endoplasmic reticulum [ 10 , 11 ]. A Trojan Horse mechanism has been proposed whereby AgNPs act as a vehicle that carries silver across the cell membrane followed by intracellular dissolution of AgNPs to release Ag + [ 19 , 20 ], resulting in ROS production, DNA damage, proteotoxic stress, and apoptosis [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

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The mechanism of cell death induced by silver nanoparticles is distinct from silver cations

et al. 2021

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Background Precisely how silver nanoparticles (AgNPs) kill mammalian cells still is not fully understood. It is not clear if AgNP-induced damage differs from silver cation (Ag+), nor is it known how AgNP damage is transmitted from cell membranes, including endosomes, to other organelles. Cells can differ in relative sensitivity to AgNPs or Ag+, which adds another layer of complexity to identifying specific mechanisms of action. Therefore, we determined if there were specific effects of AgNPs that differed from Ag+ in cells with high or low sensitivity to either toxicant. Methods Cells were exposed to intact AgNPs, Ag+, or defined mixtures of AgNPs with Ag+, and viability was assessed. The level of dissolved Ag+ in AgNP suspensions was determined using inductively coupled plasma mass spectrometry. Changes in reactive oxygen species following AgNP or Ag+ exposure were quantified, and treatment with catalase, an enzyme that catalyzes the decomposition of H2O2 to water and oxygen, was used to determine selectively the contribution of H2O2 to AgNP and Ag+ induced cell death. Lipid peroxides, formation of 4-hydroxynonenol protein adducts, protein thiol oxidation, protein aggregation, and activation of the integrated stress response after AgNP or Ag+ exposure were quantified. Lastly, cell membrane integrity and indications of apoptosis or necrosis in AgNP and Ag+ treated cells were examined by flow cytometry. Results We identified AgNPs with negligible Ag+ contamination. We found that SUM159 cells, which are a triple-negative breast cancer cell line, were more sensitive to AgNP exposure less sensitive to Ag+ compared to iMECs, an immortalized, breast epithelial cell line. This indicates that high sensitivity to AgNPs was not predictive of similar sensitivity to Ag+. Exposure to AgNPs increased protein thiol oxidation, misfolded proteins, and activation of the integrated stress response in AgNP sensitive SUM159 cells but not in iMEC cells. In contrast, Ag+ cause similar damage in Ag+ sensitive iMEC cells but not in SUM159 cells. Both Ag+ and AgNP exposure increased H2O2 levels; however, treatment with catalase rescued cells from Ag+ cytotoxicity but not from AgNPs. Instead, our data support a mechanism by which damage from AgNP exposure propagates through cells by generation of lipid peroxides, subsequent lipid peroxide mediated oxidation of proteins, and via generation of 4-hydroxynonenal (4-HNE) protein adducts. Conclusions There are distinct differences in the responses of cells to AgNPs and Ag+. Specifically, AgNPs drive cell death through lipid peroxidation leading to proteotoxicity and necrotic cell death, whereas Ag+ increases H2O2, which drives oxidative stress and apoptotic cell death. This work identifies a previously unknown mechanism by which AgNPs kill mammalian cells that is not dependent upon the contribution of Ag+ released in extracellular media. Understanding precisely which factors drive the toxicity of AgNPs is essential for biomedical applications such as cancer therapy, and of importance to identifying consequences of unintended exposures.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The mechanism of cell death induced by silver nanoparticles is distinct from silver cations

et al. 2021

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“…Gadolinium-metallofullerenol nanoparticles blocked epithelial-to-mesenchymal transition in triple-negative breast cancer (TNBC) and eliminated breast cancer stem cells (CSCs) [21]. Furthermore, we previously observed that AgNPs selectively eliminate certain TNBCs, ovarian cancer cells, and NCSLC with a mesenchymal phenotype [23,27,29,33]. Reports indicate that certain nanoparticles, including iron-core nanoparticles [70,71], titanium dioxide (TiO2) [72], ultrasmall poly (ethylene glycol)-coated silica nanoparticles [73], cobalt NPs [74], and manganese silicate nanobubbles [75], induce lipid oxidation in a variety of cell types.…”

Section: Discussionmentioning

confidence: 99%

“…We and others found that certain breast cancer cell lines are more sensitive to silver nanoparticle (AgNP) exposure than non-malignant mammary epithelial cells [23][24][25][26]. Notably, AgNP exposure increases protein oxidation and proteotoxic stress [23][24][25][27][28][29] and may cause lipid peroxidation in certain cells and organisms [30][31][32]. However, there is considerable heterogeneity in the relative sensitivity of various cancers to AgNP exposure [23][24][25]27,29,33,34], and it is not known if cancers with an EMT phenotype are more susceptible than other cancers or normal cells to proteotoxic stress or lipid peroxidation caused by exposure to AgNPs.…”

Section: Introductionmentioning

confidence: 99%

Low Doses of Silver Nanoparticles Selectively Induce Lipid Peroxidation and Proteotoxic Stress in Mesenchymal Subtypes of Triple-Negative Breast Cancer

Snyder

Rohde

Fahrenholtz

et al. 2021

Cancers

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Molecular profiling of tumors shows that triple-negative breast cancer (TNBC) can be stratified into mesenchymal (claudin-low breast cancer; CLBC) and epithelial subtypes (basal-like breast cancer; BLBC). Subtypes differ in underlying genetics and in response to therapeutics. Several reports indicate that therapeutic strategies that induce lipid peroxidation or proteotoxicity may be particularly effective for various cancers with a mesenchymal phenotype such as CLBC, for which no specific treatment regimens exist and outcomes are poor. We hypothesized that silver nanoparticles (AgNPs) can induce proteotoxic stress and cause lipid peroxidation to a greater extent in CLBC than in BLBC. We found that AgNPs were lethal to CLBCs at doses that had little effect on BLBCs and were non-toxic to normal breast epithelial cells. Analysis of mRNA profiles indicated that sensitivity to AgNPs correlated with expression of multiple CLBC-associated genes. There was no correlation between sensitivity to AgNPs and sensitivity to silver cations, uptake of AgNPs, or proliferation rate, indicating that there are other molecular factors driving sensitivity to AgNPs. Mechanistically, we found that the differences in sensitivity of CLBC and BLBC cells to AgNPs were driven by peroxidation of lipids, protein oxidation and aggregation, and subsequent proteotoxic stress and apoptotic signaling, which were induced in AgNP-treated CLBC cells, but not in BLBC cells. This study shows AgNPs are a specific treatment for CLBC and indicates that stratification of TNBC subtypes may lead to improved outcomes for other therapeutics with similar mechanisms of action.

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Assessment of the Biological Impact of Engineered Nanomaterials Using Mass Spectrometry‐Based MultiOmics Approaches

Day¹,

Zhang²,

Gaffrey³

et al. 2023

Impact of Engineered Nanomaterials in Genomics and Epigenomics

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Integrated Redox Proteomic Analysis Highlights New Mechanisms of Sensitivity to Silver Nanoparticles

Cited by 15 publications

References 64 publications

The mechanism of cell death induced by silver nanoparticles is distinct from silver cations

The mechanism of cell death induced by silver nanoparticles is distinct from silver cations

Low Doses of Silver Nanoparticles Selectively Induce Lipid Peroxidation and Proteotoxic Stress in Mesenchymal Subtypes of Triple-Negative Breast Cancer

Assessment of the Biological Impact of Engineered Nanomaterials Using Mass Spectrometry‐Based MultiOmics Approaches

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