Involvement of ERK MAP kinase in endoplasmic reticulum stress in SH-SY5Y human neuroblastoma cells

J Neurochem. 2004 Apr;89(1):232-9. doi: 10.1111/j.1471-4159.2004.02317.x.


Endoplasmic reticulum (ER) stress has increasingly come into focus as a factor contributing to neuronal injury. Although caspase-dependent mechanisms have been implicated in ER stress, the signaling pathways involved remain unclear. In this study, we examined the role of the extracellular signal-regulated kinase (ERK), a mitogen-activated protein (MAP) kinase pathway that is highly conserved in many systems for balancing cell survival and death. Prolonged treatment of the human neuroblastoma cell line SH-SY5Y with thapsigargin, an inducer of ER stress, increased cell death over 24-48 h, as measured by LDH release. Caspases were involved; increased levels of active caspase-3 and cleaved caspase substrate PARP were detected, and treatment with Z-VAD-FMK reduced thapsigargin-induced cytotoxicity. In contrast, inhibition of calpain was not protective, although calpain was activated following thapsigargin treatment. An early and transient phosphorylation of ERK1/2 occurred after thapsigargin-induced ER stress, and targeting this pathway with the MEK inhibitors U0126 or PD98059 significantly reduced cell death. Similar cytoprotection was obtained against brefeldin A, another ER stress agent. However, protection against ER stress via ERK inhibition was not accompanied by amelioration of caspase-3 activation, PARP cleavage, or DNA laddering. These data indicate that ERK may contribute to non-caspase-dependent pathways of injury after ER stress.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Brefeldin A / pharmacology
  • Carrier Proteins / metabolism
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Heat-Shock Proteins*
  • Humans
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism*
  • Molecular Chaperones*
  • Neuroblastoma / drug therapy
  • Neuroblastoma / enzymology
  • Neuroblastoma / metabolism*
  • Protein Synthesis Inhibitors / pharmacology
  • Stress, Physiological / chemically induced
  • Stress, Physiological / metabolism*
  • Thapsigargin / pharmacology


  • Carrier Proteins
  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Heat-Shock Proteins
  • Molecular Chaperones
  • Protein Synthesis Inhibitors
  • Brefeldin A
  • Thapsigargin
  • Mitogen-Activated Protein Kinases
  • Caspases
  • molecular chaperone GRP78