Phenyl acyl acids attenuate the unfolded protein response in tunicamycin-treated neuroblastoma cells

PLoS One. 2013 Aug 15;8(8):e71082. doi: 10.1371/journal.pone.0071082. eCollection 2013.

Abstract

Understanding how neural cells handle proteostasis stress in the endoplasmic reticulum (ER) is important to decipher the mechanisms that underlie the cell death associated with neurodegenerative diseases and to design appropriate therapeutic tools. Here we have compared the sensitivity of a human neuroblastoma cell line (SH-SY5H) to the ER stress caused by an inhibitor of protein glycosylation with that observed in human embryonic kidney (HEK-293T) cells. In response to stress, SH-SY5H cells increase the expression of mRNA encoding downstream effectors of ER stress sensors and transcription factors related to the unfolded protein response (the spliced X-box binding protein 1, CCAAT-enhancer-binding protein homologous protein, endoplasmic reticulum-localized DnaJ homologue 4 and asparagine synthetase). Tunicamycin-induced death of SH-SY5H cells was prevented by terminal aromatic substituted butyric or valeric acids, in association with a decrease in the mRNA expression of stress-related factors, and in the accumulation of the ATF4 protein. Interestingly, this decrease in ATF4 protein occurs without modifying the phosphorylation of the translation initiation factor eIF2α. Together, these results show that when short chain phenyl acyl acids alleviate ER stress in SH-SY5H cells their survival is enhanced.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism
  • Aspartate-Ammonia Ligase / genetics
  • Aspartate-Ammonia Ligase / metabolism
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum Stress
  • Eukaryotic Initiation Factor-2 / genetics
  • Eukaryotic Initiation Factor-2 / metabolism
  • Gene Expression Regulation / drug effects*
  • Glycosylation
  • HEK293 Cells
  • HSP40 Heat-Shock Proteins / genetics
  • HSP40 Heat-Shock Proteins / metabolism
  • Humans
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Pentanoic Acids / pharmacology*
  • Phenylbutyrates / pharmacology*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Tunicamycin / pharmacology*
  • Unfolded Protein Response / drug effects*
  • Unfolded Protein Response / genetics

Substances

  • ATF4 protein, human
  • CCAAT-Enhancer-Binding Proteins
  • DNAJA4 protein, human
  • Eukaryotic Initiation Factor-2
  • HSP40 Heat-Shock Proteins
  • NFX1 protein, human
  • Pentanoic Acids
  • Phenylbutyrates
  • Repressor Proteins
  • Tunicamycin
  • Activating Transcription Factor 4
  • Aspartate-Ammonia Ligase
  • 5-phenylvaleric acid

Grants and funding

This study was supported by the Foundation for Applied Medical Research (UTE project FIMA), Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.