Silica nanoparticles induce endoplasmic reticulum stress response, oxidative stress and activate the mitogen-activated protein kinase (MAPK) signaling pathway
| العنوان: | Silica nanoparticles induce endoplasmic reticulum stress response, oxidative stress and activate the mitogen-activated protein kinase (MAPK) signaling pathway |
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| المؤلفون: | Verena Christen, Magdalena Camenzind, Karl Fent |
| المصدر: | Toxicology Reports, Vol 1, Iss C, Pp 1143-1151 (2014) Toxicology Reports |
| بيانات النشر: | Elsevier BV, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | MAPK/ERK pathway, Health, Toxicology and Mutagenesis, eIF2α, eukaryotic initiation factor 2α, ATF-4, Activating transcription factor 4, Noxa, phorbol-12-myristate-13-acetate-induced protein 1, Toxicology, CREB, medicine.disease_cause, CHOP, CCAAT/enhancer binding protein-homologous protein, Article, MAPK, mitogen-activated protein kinase signaling pathway, p53, TP53-tumorsuppressor-gene, PERK, protein kinase like ER kinase, XBP-1, X-box binding protein 1, UPR, unfolded protein response, IFN α, interferon α, lcsh:RA1190-1270, NFκB, nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells, medicine, Protein kinase A, STAT1, signal transducer and activator of transcription 1, lcsh:Toxicology. Poisons, Proinflammatory response, Iinterferon-stimulated genes, biology, SiO2-NPs, silica nanoparticles, Tumor necrosis factor alpha, Endoplasmic reticulum, Human hepatoma cells, BiP, binding immunoglobulin protein, ISGs, interferon stiulated genes, Cell biology, TNFα, tumor necrosis factor α, IRE-1, inositol-requiring protein 1, IFN β, interferon β, ISG-15, interferon-induced 17 kDa protein, Mitogen-activated protein kinase, PP2A, protein phosphatase 2a, Immunology, ATF-6, activating transcription factor 6, biology.protein, Unfolded protein response, CREB, cAMP response element-binding protein, Signal transduction, Huh7, human hepatoma cells, IP-10, interferon gamma-induced protein 10, Oxidative stress, IRF-9, interferon regulatory factor 9 |
| الوصف: | Highlights • Silica nanoparticles (225 nm) induced ER stress and unfolded protein response. • MAPK pathway and associated genes are induced. • PP2Ac, TNFα, NFкB and interferon stimulated genes are up-regulated. • p53 is down-regulated, indicating inhibition of apoptosis. • The data suggest hepatotoxic, inflammatory and tumorigenic action of SiO2-NPs. Application of silica nanoparticles (SiO2-NPs) may result in human exposure. Here we investigate unexplored modes of action by which SiO2-NPs with average size of 225 nm act on human hepatoma cells (Huh7). We focused on the endoplasmic (ER) stress response and on mitogen-activated protein kinase (MAPK) signaling pathways. Both pathways were induced. ER stress and the associated three unfolded protein response (UPR) pathways were activated as demonstrated by significant inductions of BiP and XBP-1s and a moderate but significant induction of ATF-4 at 0.05 and 0.5 mg/ml. In addition to activation of NFкB interferon stimulated genes IP-10, IRF-9, and ISG-15 were up-regulated. As a consequence of ER stress, the pro-inflammatory cytokine TNFα and PP2Ac were induced following exposure to 0.05 mg/ml SiO2-NPs. Additionally, this occurred at 0.005 mg/ml SiO2-NPs for TNFα at 24 h. This in turn led to a strong transcriptional induction of MAP-kinases and its target genes cJun, cMyc and CREB. A strong transcriptional down-regulation of the proapoptotic gene p53 occurred at 0.05 and 0.5 mg/ml SiO2-NP. Exposure of Huh7 cells to the anti-oxidant N-acetyl cysteine reduced transcriptional induction of ER stress markers demonstrating a link between the induction of oxidative stress and ER stress. Our study demonstrates that SiO2-NPs lead to strong ER stress and UPR induction, oxidative stress, activation of MAPK signaling and down-regulation of p53. All of these activated pathways, which are analyzed here for the first time in detail, inhibit apoptosis and induce cell proliferation, which may contribute to a hepatotoxic, inflammatory and tumorigenic action of SiO2-NPs. |
| تدمد: | 2214-7500 |
| DOI: | 10.1016/j.toxrep.2014.10.023 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c57ecd7b912ae1263fdae8c13fa402bbTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c57ecd7b912ae1263fdae8c13fa402bb |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22147500 |
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| DOI: | 10.1016/j.toxrep.2014.10.023 |