Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis

Cell Death Differ. 2004 Sep;11(9):1009-16. doi: 10.1038/sj.cdd.4401436.


Apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs) is involved not only in the production of NSAID-induced gastric lesions but also in the antitumor activity of these drugs. The endoplasmic reticulum (ER) stress response is a cellular mechanism that aids in protecting the ER against ER stressors and is involved in ER stressor-induced apoptosis. Here, we examine the relationship between this response and NSAID-induced apoptosis in cultured guinea-pig gastric mucosal cells. Exposure of cells to indomethacin, a commonly used NSAID, induced GRP78 as well as CHOP, a transcription factor involved in apoptosis. Three factors that positively regulate CHOP expression (ATF6, ATF4 and XBP-1) were activated and/or induced by indomethacin. NSAIDs other than indomethacin (diclofenac, ibuprofen and celecoxib) also induced CHOP. Monitoring of the transcriptional activities of ATF6 and CHOP by luciferase assay revealed that both were stimulated in the presence of indomethacin. Furthermore, indomethacin-induced apoptosis was suppressed in cultured guinea-pig gastric mucosal cells by expression of the dominant-negative form of CHOP, or in peritoneal macrophages from CHOP-deficient mice. These results suggest that ER stress response-related proteins, particularly CHOP, are involved in NSAID-induced apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Apoptosis*
  • Blotting, Northern
  • Celecoxib
  • Cell Line
  • Cell Survival
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Diclofenac / pharmacology
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum / drug effects*
  • Endoplasmic Reticulum / pathology*
  • Enzyme Activation
  • Gastric Mucosa / pathology
  • Genes, Reporter
  • Guinea Pigs
  • Heat-Shock Proteins / metabolism
  • Hydrogen Peroxide / pharmacology
  • Ibuprofen / pharmacology
  • Immunoblotting
  • Indomethacin / pharmacology
  • Luciferases / metabolism
  • Macrophages / metabolism
  • Microscopy, Fluorescence
  • Molecular Chaperones / metabolism
  • Plasmids / metabolism
  • Pyrazoles / pharmacology
  • RNA, Messenger / metabolism
  • Regulatory Factor X Transcription Factors
  • Sulfonamides / pharmacology
  • Time Factors
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transfection
  • X-Box Binding Protein 1


  • Anti-Inflammatory Agents, Non-Steroidal
  • DNA-Binding Proteins
  • Heat-Shock Proteins
  • Molecular Chaperones
  • Pyrazoles
  • RNA, Messenger
  • Regulatory Factor X Transcription Factors
  • Sulfonamides
  • Transcription Factors
  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • Diclofenac
  • Activating Transcription Factor 4
  • Hydrogen Peroxide
  • Luciferases
  • Celecoxib
  • Ibuprofen
  • Indomethacin
  • molecular chaperone GRP78