Arsenite‐induced endoplasmic reticulum‐dependent apoptosis through disturbance of calcium homeostasis in H<scp>BE</scp> cell line

Chen, Chengzhi; Gu, Shiyan; Jiang, Xuejun; Zhang, Zunzhen

doi:10.1002/tox.22226

Cited by 17 publications

(6 citation statements)

References 54 publications

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“…Since sodium arsenite has been shown to cause ER stress in certain cell types (Hou et al ., 2013; Chen et al ., 2015), we next analyzed the three major ER stress response pathways (ATF6, IRE1, and PERK) to determine if sodium arsenite blockage of autophagy was associated with increased ER stress. We treated NIH 3T3, HeLa, HEK 293, and HEMn-LP cells with sodium arsenite (0, 0.25, 0.5, 1, or 2 µM) for 0.5, 1, 2 or 4 h, and measured ATF6 cleavage, an indicator of activation of the ATF6 arm, XBP1s levels, an indicator of activation of the IRE1 arm, and phosphorylation of EIF2S1/eIF2α, an indicator of activation of the PERK arm, by immunoblot analysis (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

Low-level arsenic causes proteotoxic stress and not oxidative stress

Dodson

Vega

Harder

et al. 2018

Toxicology and Applied Pharmacology

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Prolonged exposure to arsenic has been shown to increase the risk of developing a number of diseases, including cancer and type II diabetes. Arsenic is present throughout the environment in its inorganic forms, and the level of exposure varies greatly by geographical location. The current recommended maximum level of arsenic exposure by the EPA is 10μg/L, but levels>50-1000μg/L have been detected in some parts of Asia, the Middle East, and the Southwestern United States. One of the most important steps in developing treatment options for arsenic-linked pathologies is to understand the cellular pathways affected by low levels of arsenic. Here, we show that acute exposure to non-lethal, low-level arsenite, an environmentally relevant arsenical, inhibits the autophagy pathway. Furthermore, arsenite-induced autophagy inhibition initiates a transient, but moderate ER stress response. Significantly, low-level arsenite exposure does not exhibit an increase in oxidative stress. These findings indicate that compromised autophagy, and not enhanced oxidative stress occurs early during arsenite exposure, and that restoring the autophagy pathway and proper proteostasis could be a viable option for treating arsenic-linked diseases. As such, our study challenges the existing paradigm that oxidative stress is the main underlying cause of pathologies associated with environmental arsenic exposure.

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Section: Resultsmentioning

confidence: 99%

Low-level arsenic causes proteotoxic stress and not oxidative stress

Dodson

Vega

Harder

et al. 2018

Toxicology and Applied Pharmacology

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“…It was found that the AsO 2 − -induced superoxide increase in human myeloid leukemia U937 cells has two contrary pathways: the first leads to the promotion of Nrf2 signaling followed by GSH biosynthesis; the second results in DNA damage and MPTP opening with rapid and massive apoptotic cell death [274,275]. As(III) (AsO 2 − and As 2 O 3 ) increased the intracellular Ca 2+ concentration and mitochondrial dysfunction due to Ca 2+ mobilizing from the ER in human myeloid leukemia U937 cells, human bronchial epithelial HBE cells, and human umbilical and bone marrow mesenchymal stem cells [276][277][278].…”

Section: Al(iii) Ga(iii) and In(iiimentioning

confidence: 99%

Mitochondrial Oxidative Stress Is the General Reason for Apoptosis Induced by Different-Valence Heavy Metals in Cells and Mitochondria

Korotkov

2023

IJMS

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This review analyzes the causes and consequences of apoptosis resulting from oxidative stress that occurs in mitochondria and cells exposed to the toxic effects of different-valence heavy metals (Ag+, Tl+, Hg2+, Cd2+, Pb2+, Al3+, Ga3+, In3+, As3+, Sb3+, Cr6+, and U6+). The problems of the relationship between the integration of these toxic metals into molecular mechanisms with the subsequent development of pathophysiological processes and the appearance of diseases caused by the accumulation of these metals in the body are also addressed in this review. Such apoptosis is characterized by a reduction in cell viability, the activation of caspase-3 and caspase-9, the expression of pro-apoptotic genes (Bax and Bcl-2), and the activation of protein kinases (ERK, JNK, p53, and p38) by mitogens. Moreover, the oxidative stress manifests as the mitochondrial permeability transition pore (MPTP) opening, mitochondrial swelling, an increase in the production of reactive oxygen species (ROS) and H2O2, lipid peroxidation, cytochrome c release, a decline in the inner mitochondrial membrane potential (ΔΨmito), a decrease in ATP synthesis, and reduced glutathione and oxygen consumption as well as cytoplasm and matrix calcium overload due to Ca2+ release from the endoplasmic reticulum (ER). The apoptosis and respiratory dysfunction induced by these metals are discussed regarding their interaction with cellular and mitochondrial thiol groups and Fe2+ metabolism disturbance. Similarities and differences in the toxic effects of Tl+ from those of other heavy metals under review are discussed. Similarities may be due to the increase in the cytoplasmic calcium concentration induced by Tl+ and these metals. One difference discussed is the failure to decrease Tl+ toxicity through metallothionein-dependent mechanisms. Another difference could be the decrease in reduced glutathione in the matrix due to the reversible oxidation of Tl+ to Tl3+ near the centers of ROS generation in the respiratory chain. The latter may explain why thallium toxicity to humans turned out to be higher than the toxicity of mercury, lead, cadmium, copper, and zinc.

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“…Various toxicants have been found to be able to induce ER stress (Hosohata et al, 2019). Arsenate has been shown to induce ER stress by elevating the expression levels of GRP78 and CHOP (Chen et al, 2017). Consistent with these studies, we found that the expressions of ATF6, IRE1, CHOP, and GRP78 were gradually increased in a concentration-dependent manner after Pb(Ac) 2 exposure, indicating that Pb(Ac) 2 can induce ER stress by the activation of the ATF6 and IRE1 signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

The role of endoplasmic reticulum stress in lead (Pb)-induced mitophagy of HEK293 cells

et al. 2020

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It is well-documented that lead (Pb) toxicity can affect almost all systems in living organisms. It can induce selective autophagy of mitochondria (mitophagy) by triggering reactive oxygen species production. Emerging evidence has suggested that Pb-induced autophagy can also be activated by the endoplasmic reticulum (ER) stress pathway. However, the interplay between ER stress and mitophagy remains to be elucidated. In this study, human embryonic kidney HEK293 cells were employed to investigate the role of ER stress in Pb-induced mitophagy. The results showed that the cell viability was decreased and cell damage was induced after exposure to Pb (0, 0.5, 1, 2, and 4 mM) for 24 h in a dose-dependent manner. Moreover, the expression of LC3-Ⅱ was significantly increased, and the expression of HSP60 was dramatically decreased after exposure to 1 mM and 2 mM Pb, indicating the induction of mitophagy following Pb exposure. Meanwhile, the expressions of activating transcription factor 6, inositol-requiring protein-1α, CCAAT/enhancer binding protein homologous protein, and glucose-regulated protein 78 were dramatically increased after Pb treatment, signifying the initiation of ER stress. Notably, the mitophagic effect was significantly compromised when ER stress was inhibited by 0.5 mM 4-phenylbutyrate, which was evidenced by lesser decreases in HSP60 expression and level of LC3-Ⅱ, suggesting Pb-induced mitophagy may be activated by the ER stress. Taken together, these findings provide a better understanding of Pb toxicity and suggest that Pb-induced ER stress may play a regulatory role in the upstream of mitophagy.

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Arsenite‐induced endoplasmic reticulum‐dependent apoptosis through disturbance of calcium homeostasis in HBE cell line

Cited by 17 publications

References 54 publications

Low-level arsenic causes proteotoxic stress and not oxidative stress

Low-level arsenic causes proteotoxic stress and not oxidative stress

Mitochondrial Oxidative Stress Is the General Reason for Apoptosis Induced by Different-Valence Heavy Metals in Cells and Mitochondria

The role of endoplasmic reticulum stress in lead (Pb)-induced mitophagy of HEK293 cells

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