Endoplasmic reticulum stress signaling is involved in silver nanoparticles-induced apoptosis

Int J Biochem Cell Biol. 2012 Jan;44(1):224-32. doi: 10.1016/j.biocel.2011.10.019. Epub 2011 Nov 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / antagonists & inhibitors
  • Activating Transcription Factor 6 / biosynthesis
  • Activating Transcription Factor 6 / genetics
  • Activating Transcription Factor 6 / metabolism
  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Calcium / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cricetinae
  • Endoplasmic Reticulum Stress / drug effects*
  • Endoplasmic Reticulum Stress / physiology
  • Endoribonucleases / biosynthesis
  • Endoribonucleases / genetics
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Humans
  • Liver / cytology
  • Liver / drug effects
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Metal Nanoparticles / chemistry*
  • Mitochondria / metabolism
  • Oxidative Stress
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / genetics
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • Signal Transduction
  • Silver / chemistry
  • Silver / pharmacology*
  • Transcription Factor CHOP / antagonists & inhibitors
  • Transcription Factor CHOP / metabolism
  • Transfection
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism

Substances

  • ATF6 protein, human
  • Activating Transcription Factor 6
  • DDIT3 protein, human
  • Membrane Proteins
  • RNA, Small Interfering
  • Transcription Factor CHOP
  • Silver
  • ERN2 protein, human
  • PERK kinase
  • Protein-Serine-Threonine Kinases
  • eIF-2 Kinase
  • Endoribonucleases
  • Calcium