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

S Tsutsumi1, T Gotoh, W Tomisato

  • 1Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan.

Cell Death and Differentiation
|May 8, 2004
PubMed

Insights

Nonsteroidal anti-inflammatory drugs (NSAIDs) trigger apoptosis via endoplasmic reticulum (ER) stress. The study shows that CHOP, an ER stress response protein, is crucial for NSAID-induced apoptosis in gastric cells.

Area of Science:

  • Cellular Biology
  • Pharmacology
  • Molecular Biology

Background:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) induce apoptosis, contributing to gastric lesions and antitumor effects.
  • The endoplasmic reticulum (ER) stress response is a cellular defense mechanism involved in apoptosis.
  • The interplay between ER stress and NSAID-induced apoptosis requires further elucidation.

Purpose of the Study:

  • To investigate the role of the ER stress response in NSAID-induced apoptosis.
  • To determine if ER stress-related proteins are involved in NSAID-induced apoptosis in gastric mucosal cells.

Main Methods:

  • Cultured guinea-pig gastric mucosal cells were exposed to indomethacin and other NSAIDs.
  • Expression of ER stress markers (GRP78, CHOP) and related transcription factors (ATF6, ATF4, XBP-1) was analyzed.
  • Transcriptional activity of ATF6 and CHOP was measured using luciferase assays.
  • Apoptosis was assessed in CHOP-deficient cells and cells expressing dominant-negative CHOP.

Main Results:

  • Indomethacin induced GRP78 and CHOP expression in gastric mucosal cells.
  • NSAIDs (diclofenac, ibuprofen, celecoxib) also induced CHOP.
  • Indomethacin activated ATF6, ATF4, and XBP-1, and stimulated ATF6 and CHOP transcriptional activity.
  • CHOP deficiency or dominant-negative CHOP expression suppressed indomethacin-induced apoptosis.

Conclusions:

  • The ER stress response, particularly the transcription factor CHOP, plays a significant role in NSAID-induced apoptosis.
  • NSAIDs activate ER stress pathways leading to apoptosis in gastric mucosal cells.
  • Targeting ER stress pathways may offer therapeutic strategies for NSAID-related gastric issues or enhance antitumor effects.

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