title: Endoplasmic reticulum stress signaling is involved in silver nanoparticles-induced apoptosis.
abstract: Although silver nanoparticles (AgNPs) have been reported to exert strong acute toxic effects on various cultured cells by inducing oxidative stress, the molecular mechanisms by which AgNPs-damaged cells are unknown. Because the endoplasmic reticulum (ER) may play an important role in the response to oxidative stress-induced damage and is quite sensitive to oxidative damage, we hypothesized that AgNPs may exert cytotoxic effects on cells by modulating ER stress. In our study, AgNPs resulted in cytotoxicity and apoptotic cell death when analyzing cell viability, DNA fragmentation and the apoptotic sub-G(1) population. Flow cytometry and confocal microscopy indicated that the cells were sensitive to AgNPs with respect to the induction of mitochondrial Ca(2+) overloading and enhancement of ER stress. AgNPs induced a number of signature ER stress markers, including phosphorylation of RNA-dependent protein kinase-like ER kinase (PERK) and its downstream eukaryotic initiation factor 2α, phosphorylation of inositol-requiring protein 1 (IRE1), splicing of ER stress-specific X-box transcription factor-1, cleavage of activating transcription factor 6 (ATF6) and up-regulation of glucose-regulated protein-78 and CCAAT/enhancer-binding protein-homologous protein (CHOP/GADD153). Down-regulation of PERK, IRE1 and ATF6 expression using siRNA significantly decreased AgNPs-induced the enhancement of ER stress. In addition, down-regulation of CHOP expression with siRNA CHOP attenuated AgNPs-induced apoptosis. Taken together, the present study supports an important role for the ER stress response in mediating AgNPs-induced apoptosis.
authors: School of Medicine and Applied Radiological Science Research Institute, Jeju National University, Jeju, Republic of Korea.
authors: Rui
authors: R
authors: Zhang
authors: Mei Jing
authors: MJ
authors: Piao
authors: Ki Cheon
authors: KC
authors: Kim
authors: Areum Daseul
authors: AD
authors: Kim
authors: Jeong-Yun
authors: JY
authors: Choi
authors: Jinhee
authors: J
authors: Choi
authors: Jin Won
authors: JW
authors: Hyun
mesh_terms: D051702:Activating Transcription Factor 6 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D004722:Endoribonucleases / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D053768:Metal Nanoparticles / Q000737:chemistry*; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction; D012834:Silver / Q000737:chemistry / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D002118:Calcium; D004722:Endoribonucleases; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D012834:Silver; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497111:ATF6 protein, human; C497249:DDIT3 protein, human; C403982:ERN2 protein, human