Role of reactive oxygen species-dependent protein aggregation in metabolic stress-induced necrosis

Kim, Cho Hee; Jeon, Hyun Min; Lee, Su Yeon; Jeong, Eunwook; Ju, Min Kyung; Park, Bum-Joon; Park, Hye Gyeong; Lim, Sung‐Chul; Kang, Ho Sung

doi:10.3892/ijo_00000657

Cited by 12 publications

(2 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, Ag + treatment caused apoptosis at lower doses in iMEC cells compared to SUM159 cells. Accumulation of 4-HNE and the resulting buildup of protein aggregates in the cell are highly toxic and have been shown to initiate necrotic cell death [ 64 , 65 ], whereas cell death caused by excess ROS is more often mediated by apoptosis [ 66 ]. Therefore, the difference in cell death pathways could be due to the induction of lipid peroxidation by AgNPs but not Ag + .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

show abstract

“…These results are accordance with the findings of Kim et al, who showed that metabolic stress induces the formation of protein aggregates in A549 cells. 65 Additionally, two-photon fluorescence microscopy allows a deeper penetration of the excitation laser beam into tissues and cell spheroids. Figure 9 shows that compound 1 can be taken up by cells in spheroids.…”

Section: Resultsmentioning

confidence: 99%

A Fluorescent Probe for Protein Misfolding and Aggregation Due to Oxidative Stress Based on a 7-Azaindole-BODIPY Derivative

Herrera-Ochoa,

Llano,

Ripoll

et al. 2024

Preprint

View full text Add to dashboard Cite

The development of new fluorescent probes as molecular sensors is a critical step for the understanding of molecular mechanisms. Probes based on BODIPY offer remarkable versatility in molecular sensing due to their unique properties. BODIPY-based probes exhibit high fluorescence quantum yields, exceptional photostability, and tunable absorption/emission wavelengths. Here, we report the synthesis and evaluation of a novel 7-azaindole-BODIPY derivative to probe hydrophobic proteins as well as protein misfolding and aggregation. In organic solvents, this compound exhibits two emissive excited states efficiently interconverting. In contrast, within aqueous environments, the formation of molecular aggregates induces distinct photophysical properties. The complex photophysics of this 7-azaindole-BODIPY derivate were used as a starting point to explore its sensing applications. In presence of albumin, the monomeric form of the probe is stabilized in the hydrophobic regions of the protein, leading to a significant increase of both the fluorescence emission intensity and lifetime. A similar effect was observed when the probe interacts with protein aggregates. Notably, the fluorescence emission is less sensitive to the presence of other macromolecules such as pepsin, DNA, Ficoll 40, and coconut oil. Fluorescence lifetime imaging microscopy (FLIM) and two-photon fluorescence microscopy performed on breast cancer cells (MCF-7) and lung cancer cells (A549) incubated with this probe revealed longer fluorescence lifetimes and higher emission intensity upon oxidative stress. It is known that cellular stress leads to the accumulation and aggregation of misfolded proteins. Protein misfolding in MCF-7 cells under oxidative stress conditions was confirmed by synchrotron FTIR microspectroscopy. These results show that protein misfolding and aggregation triggered by oxidative stress can be monitored using the probe here developed.

show abstract

Inhibition of breast cancer cell growth by methyl pyropheophenylchlorin photodynamic therapy is mediated though endoplasmic reticulum stress‐induced autophagy in vitro and vivo

Zhu

Tian

et al. 2018

Cancer Medicine

View full text Add to dashboard Cite

Autophagy and ER stress participated in the inhibition of MPPa‐PDT on tumor growth, but the molecular links between them remain undefined. We just explore the molecular mechanism between them in vitro and vivo. CCK‐8 assay and flow cytometer were used to detect the cytotoxicity and mode of cell death after MPPa‐PDT. Furthermore, the role of autophagy was verified in MPPa‐PDT. Confocal microscopy was used to show the intracellular distribution of MPPa. ER stress markers and PERK signaling pathway were detected by western blot. While in vivo, tumor histology and immunohistochemistry were performed to show the effect of MPPa‐PDT in mice. After MPPa‐PDT, cells viability decreased in dose‐dependent manner. Besides, the cell apoptosis increased along with the increasing of Beclin‐1and LC3B II but declining of P62. When pretreated with 3‐MA, LC3B II formation and the cytotoxicity declined. MPPa‐PDT caused increasing of ER stress markers (GRP78, CHOP) as MPPa accumulated in ER. However, pretreatment with ER stress inhibitor 4PBA, the expression of GRP78 and LC3B II was blocked but the PERK signaling pathway activated and the expression of P62 increased. In vivo, the tumor growth was significantly inhibited by MPPa‐PDT. Besides, the appearance of ER stress and autophagy was further demonstrated by immunohistochemistry. Our findings demonstrate that autophagy mediated by MPPa‐PDT was regulated by ER stress, via PERK signaling pathway, to kill MDA‐MB‐231 cells in vitro and vivo.

show abstract

Role of reactive oxygen species-dependent protein aggregation in metabolic stress-induced necrosis

Cited by 12 publications

References 29 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

A Fluorescent Probe for Protein Misfolding and Aggregation Due to Oxidative Stress Based on a 7-Azaindole-BODIPY Derivative

Inhibition of breast cancer cell growth by methyl pyropheophenylchlorin photodynamic therapy is mediated though endoplasmic reticulum stress‐induced autophagy in vitro and vivo

Contact Info

Product

Resources

About