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.
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Abbreviations
- ASK1:
-
apoptosis signal-regulating kinase 1
- ATF:
-
activating transcription factor
- CHOP:
-
C/EBP homologous transcription factor
- COX:
-
cyclooxygenase
- EGFP:
-
enhanced green fluorescent protein
- ER:
-
endoplasmic reticulum
- ERSE:
-
ER stress response element
- FBS:
-
fetal bovine serum
- GRP:
-
glucose-regulated protein
- IRE1:
-
protein-kinase and site-specific endoribonuclease
- JNK:
-
c-jun NH2-terminal kinase
- MTT:
-
3-(4, 5-dimethyl-thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide
- NSAIDs:
-
nonsteroidal anti-inflammatory drugs
- PEK:
-
pancreatic eIF2 kinase
- PERK:
-
protein kinase R-like ER kinase
- PG:
-
prostaglandin
- TRAF2:
-
tumor necrosis factor receptor-associated factor
- UPR:
-
unfolded protein response
- XBP-1:
-
X box binding protein
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Acknowledgements
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Health, Labour, and Welfare of Japan. We thank Dr. K Mori (Kyoto University) and S Akira (Osaka University) for the antibody against ATF6 and the expression plasmid for the dominant-negative form of CHOP, respectively.
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Tsutsumi, S., Gotoh, T., Tomisato, W. et al. Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis. Cell Death Differ 11, 1009–1016 (2004). https://doi.org/10.1038/sj.cdd.4401436
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DOI: https://doi.org/10.1038/sj.cdd.4401436
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