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

S. Tsutsumi, T. Gotoh, W. Tomisato, S. Mima, T. Hoshino, H. J. Hwang, H. Takenaka, T. Tsuchiya, M. Mori, T. Mizushima

Research output: Contribution to journalArticle

177 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1009-1016
Number of pages8
JournalCell Death and Differentiation
Volume11
Issue number9
DOIs
Publication statusPublished - 2004 Sep
Externally publishedYes

Fingerprint

Endoplasmic Reticulum Stress
Indomethacin
Anti-Inflammatory Agents
Apoptosis
Endoplasmic Reticulum
Pharmaceutical Preparations
Celecoxib
Stomach
Guinea Pigs
Transcription Factor CHOP
Gastrointestinal Agents
Diclofenac
Ibuprofen
Peritoneal Macrophages
Luciferases
Antineoplastic Agents
Proteins

Keywords

  • Apoptosis
  • CHOP
  • Endoplasmic reticulum
  • Gastric mucosal cells
  • NSAIDs

ASJC Scopus subject areas

  • Cell Biology

Cite this

Tsutsumi, S., Gotoh, T., Tomisato, W., Mima, S., Hoshino, T., Hwang, H. J., ... Mizushima, T. (2004). Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis. Cell Death and Differentiation, 11(9), 1009-1016. https://doi.org/10.1038/sj.cdd.4401436

Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis. / Tsutsumi, S.; Gotoh, T.; Tomisato, W.; Mima, S.; Hoshino, T.; Hwang, H. J.; Takenaka, H.; Tsuchiya, T.; Mori, M.; Mizushima, T.

In: Cell Death and Differentiation, Vol. 11, No. 9, 09.2004, p. 1009-1016.

Research output: Contribution to journalArticle

Tsutsumi, S, Gotoh, T, Tomisato, W, Mima, S, Hoshino, T, Hwang, HJ, Takenaka, H, Tsuchiya, T, Mori, M & Mizushima, T 2004, 'Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis', Cell Death and Differentiation, vol. 11, no. 9, pp. 1009-1016. https://doi.org/10.1038/sj.cdd.4401436
Tsutsumi, S. ; Gotoh, T. ; Tomisato, W. ; Mima, S. ; Hoshino, T. ; Hwang, H. J. ; Takenaka, H. ; Tsuchiya, T. ; Mori, M. ; Mizushima, T. / Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis. In: Cell Death and Differentiation. 2004 ; Vol. 11, No. 9. pp. 1009-1016.
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