The critical role of autophagy in cadmium-induced immunosuppression regulated by endoplasmic reticulum stress-mediated calpain activation in RAW264.7 mouse monocytes

So, Keum Young; Lee, Byung‐Hoon; Oh, Seon-Hee

doi:10.1016/j.tox.2017.10.016

Cited by 42 publications

(17 citation statements)

References 43 publications

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“…Interestingly, our previous data provided a possible link between LA and the decreased calcium content of brain tissue in LA-treated P301S Tau transgenic mice [19]. Combined with our current data, these observations suggest that HDI treatment leads to calcium-dependent calpain 1 activation, a decrease in the number of mitochondria, and subsequent activation of autophagy and apoptosis [73,74]. Furthermore, the protein expression levels of Beclin-1, LC3A/B, and p62, several reliable markers of autophagy [41], were significantly higher in HDI-treated mice than those in the respective controls.…”

Section: Discussionsupporting

confidence: 80%

Iron Exposure and the Cellular Mechanisms Linked to Neuron Degeneration in Adult Mice

Chai

Zhang

et al. 2019

Cells

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Although the causal relationship between Alzheimer’s disease (AD) and iron overload remains unclear, iron dyshomeostasis or improper transport mechanisms are speculated to lead to the accumulation of this neurotoxic metal in the hippocampal formation and other cerebral areas related to neurodegenerative diseases, resulting in the formation of reactive oxygen species (ROS) and, ultimately, cell death. In this study, exposure to high dietary iron (HDI) revealed no significant difference in the number of iron-positive cells and iron content in the cortex and hippocampal region between wild-type (WT) and APP/PS1 mice; however, compared with the control mice, the HDI-treated mice exhibited upregulated divalent metal transporter 1 (DMT1) and ferroportin (Fpn) expression, and downregulated transferrin receptor (TFR) expression. Importantly, we confirmed that there were significantly fewer NeuN-positive neurons in both APP/PS1 and WT mice given HDI, than in the respective controls. Moreover, this iron-induced neuron loss may involve increased ROS and oxidative mitochondria dysfunction, decreased DNA repair, and exacerbated apoptosis and autophagy. Although HDI administration might trigger protective antioxidant, anti-apoptosis, and autophagy signaling, especially in pathological conditions, these data clearly indicate that chronic iron exposure results in neuronal loss due to apoptosis, autophagy, and ferroptosis, hence increasing the risk for developing AD.

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Section: Discussionsupporting

confidence: 80%

Iron Exposure and the Cellular Mechanisms Linked to Neuron Degeneration in Adult Mice

Chai

Zhang

et al. 2019

Cells

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“…However, apoptosis was significantly reduced in the cells cotreated with si- CASC9 and the autophagy inhibitor, indicating that silencing CASC9 induced autophagy as a pro-death response. The current study found that autophagy can regulate early apoptosis 47,48 . For example, Fan et al 48 found resveratrol-induced autophagy enhances early apoptosis in HL-60 cells.…”

Section: Discussionsupporting

confidence: 50%

Increased expression of lncRNA CASC9 promotes tumor progression by suppressing autophagy-mediated cell apoptosis via the AKT/mTOR pathway in oral squamous cell carcinoma

et al. 2019

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Recent studies showed that lncRNA CASC9 was upregulated and acted as an oncogene in a variety of tumors. However, the expression and biological functions of CASC9 in oral squamous cell carcinoma (OSCC) remain unknown. In this study, we found for the first time that CASC9 was remarkably upregulated in OSCC tissues and cell lines compared with paired noncancerous tissues and normal oral epithelial cells. Highly expressed CASC9 is strongly associated with tumor size, clinical stage, regional lymph node metastasis and overall survival time in OSCC patients. In vitro, CASC9 knockdown in OSCC cells SCC15 and CAL27 significantly promotes autophagy and apoptosis, while inhibiting proliferation. Moreover, the expression levels of p-AKT, p-mTOR, P62 and BCL-2 were significantly decreased, while the expression levels of BAX and the LC3BII/LC3BI ratio were increased in CASC9-knockdown SCC15 and CAL27 cells. After the addition of the AKT activator SC79 in CASC9-knockdown SCC15 and CAL27 cells, we found that the increased autophagy and apoptosis were remarkably rescued. Furthermore, the increased apoptosis was remarkably rescued in CASC9-knockdown OSCC cells treated with the autophagy inhibitor Autophinib. In addition, CASC9 depletion suppressed tumor growth in vivo. In conclusion, our findings demonstrate that lncRNA CASC9 promotes OSCC progression through enhancing cell proliferation and suppressing autophagy-mediated cell apoptosis via the AKT/mTOR pathway. CASC9 could potentially be used as a valuable biomarker for OSCC diagnosis and prognosis.

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“…Accumulating studies have indicated that autophagy is involved in either cell protection or cell death depending on the stress conditions. We previously showed that Cd-induced autophagy promoted apoptosis in RAW264.7 cells 33 . To investigate the role of autophagy in Cd-induced Fas signaling, autophagy was inhibited with chemical inhibitors, including BaF1 or chloroquine (CQ) before adding Cd for 12 h, when there is a peak in polyUb-p62 level.…”

Section: Resultsmentioning

confidence: 96%

“…Cd toxicity is associated with different modes of cell death, including autophagy, apoptosis, and necrosis, which can impair the immune response 32 . We previously found that Cd affects the immune response via autophagy-mediated apoptosis in RAW264.7 cells 33 . Furthermore, Fas plays an important role in quality control of immune cells including macrophage 34 .…”

Section: Introductionmentioning

confidence: 98%

Polyubiquitination of p62/SQSTM1 is a prerequisite for Fas/CD95 aggregation to promote caspase-dependent apoptosis in cadmium-exposed mouse monocyte RAW264.7 cells

Jung

2019

Sci Rep

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Cadmium(Cd) induces cytotoxicity via autophagy-induced apoptosis in non-activated mouse monocytes; however, the molecular mechanism remains unclear. Here, we show that autophagy induces Fas (CD95/APO-1)-mediated apoptosis by promoting accumulation of p62/SQSTM1 in response to Cd. Cd produced tumor necrosis factor (TNF)-α, peaking at 6 h, and exhibiting a concentration-dependent increase. Immunoblot analysis revealed polyubiquitinated (polyUb) full-length Fas (antibody clone G-9) and reduced cytosolic Fas (antibody clone M-20) in Cd-exposed RAW264.7 cells. The accumulation of polyUb-Fas was transient and positively correlated with polyUb-p62 and polyUb-proteins. Autophagy inhibition via chemical and genetic modulation suppressed Cd-induced polyUb-p62, polyUb-Fas, and polyUb-protein levels, whereas the level of cytosolic Fas recovered to that of the control. Immunofluorescence (IF) staining for full-length Fas, p62, and ubiquitin revealed an aggregated pattern in Cd-induced apoptotic cells, which was inhibited by blocking autophagy. Fas colocalized with microtubule-associated protein 1 light chain (LC)-3B. IF staining and immunoprecipitation assays revealed colocalization and interaction among p62, Ub, and Fas. Knockdown of p62 reduced the binding of Ub and Fas. Together, these data suggest that polyUb-p62 targets Fas and recruits it to autophagosomes, where Fas transiently aggregates to promote apoptosis and is degraded with polyUb-p62. In conclusion, autophagy regulates C-terminal cytosolic Fas aggregation via p62 polyubiquitination, which is required for apoptosis and may play a critical role in the production of select cytokines.

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The critical role of autophagy in cadmium-induced immunosuppression regulated by endoplasmic reticulum stress-mediated calpain activation in RAW264.7 mouse monocytes

Cited by 42 publications

References 43 publications

Iron Exposure and the Cellular Mechanisms Linked to Neuron Degeneration in Adult Mice

Iron Exposure and the Cellular Mechanisms Linked to Neuron Degeneration in Adult Mice

Increased expression of lncRNA CASC9 promotes tumor progression by suppressing autophagy-mediated cell apoptosis via the AKT/mTOR pathway in oral squamous cell carcinoma

Polyubiquitination of p62/SQSTM1 is a prerequisite for Fas/CD95 aggregation to promote caspase-dependent apoptosis in cadmium-exposed mouse monocyte RAW264.7 cells

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