Involvement of intracellular Ca2+ levels in nonsteroidal anti-inflammatory drug-induced apoptosis

Ken Ichiro Tanaka, Wataru Tomisato, Tatsuya Hoshino, Tomoaki Ishihara, Takushi Namba, Mayuko Aburaya, Takashi Katsu, Keitarou Suzuki, Shinji Tsutsumi, Tohru Mizushima

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Abstract

We recently reported that nonsteroidal anti-inflammatory drug (NSAIB)-induced gastric lesions involve NSAID-induced apoptosis of gastric mucosal cells, which in turn involves the endoplasmic reticulum stress response, in particular the up-regulation of CCAAT/enhancer-binding protein homologous transcription factor (CHOP). In this study, we have examined the molecular mechanism governing this NSAID-induced apoptosis in primary cultures of gastric mucosal cells. Various NSAIDs showed membrane permeabilization activity that correlated with their apoptosis-inducing activity. Various NSAIDs, particularly celecoxib, also increased intracellular Ca2+ levels. This increase was accompanied by K+ efflux from cells and was virtually absent when extracellular Ca2+ had been depleted. These data indicate that the increase in intracellular Ca2+ levels that is observed in the presence of NSAIDs is due to the stimulation of Ca2+ influx across the cytoplasmic membrane, which results from their membrane permeabilization activity. An intracellular Ca2+ chelator partially inhibited celecoxib-induced release of cytochrome c from mitochondria, reduced the magnitude of the celecoxib-induced decrease in mitochondrial membrane potential and inhibited celecoxib-induced apoptotic cell death. It is therefore likely that an increase in intracellular Ca2+ levels is involved in celecoxib-induced mitochondrial dysfunction and the resulting apoptosis. ATI inhibitor of calpain, a Ca2+-dependent cysteine protease, partially suppressed mitochondrial dysfunction and apoptosis in the presence of celecoxib. Celecoxib-dependent CHOP-induction was partially inhibited by the intracellular Ca2+ chelator but not by the calpain inhibitor. These results suggest that Ca2+-stimulated calpain activity and CHOP expression play important roles in celecoxib-induced apoptosis in gastric mucosal cells.

Original languageEnglish
Pages (from-to)31059-31067
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number35
DOIs
Publication statusPublished - 2005 Sep 2
Externally publishedYes

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Celecoxib
Anti-Inflammatory Agents
Apoptosis
Non-Steroidal Anti-Inflammatory Agents
Pharmaceutical Preparations
Stomach
Membranes
Chelating Agents
Transcription Factor CHOP
CCAAT-Enhancer-Binding Proteins
Mitochondria
Endoplasmic Reticulum Stress
Calpain
Cysteine Proteases
Mitochondrial Membrane Potential
Cell death
Cytochromes c

ASJC Scopus subject areas

  • Biochemistry

Cite this

Tanaka, K. I., Tomisato, W., Hoshino, T., Ishihara, T., Namba, T., Aburaya, M., ... Mizushima, T. (2005). Involvement of intracellular Ca2+ levels in nonsteroidal anti-inflammatory drug-induced apoptosis. Journal of Biological Chemistry, 280(35), 31059-31067. https://doi.org/10.1074/jbc.M502956200

Involvement of intracellular Ca2+ levels in nonsteroidal anti-inflammatory drug-induced apoptosis. / Tanaka, Ken Ichiro; Tomisato, Wataru; Hoshino, Tatsuya; Ishihara, Tomoaki; Namba, Takushi; Aburaya, Mayuko; Katsu, Takashi; Suzuki, Keitarou; Tsutsumi, Shinji; Mizushima, Tohru.

In: Journal of Biological Chemistry, Vol. 280, No. 35, 02.09.2005, p. 31059-31067.

Research output: Contribution to journalArticle

Tanaka, KI, Tomisato, W, Hoshino, T, Ishihara, T, Namba, T, Aburaya, M, Katsu, T, Suzuki, K, Tsutsumi, S & Mizushima, T 2005, 'Involvement of intracellular Ca2+ levels in nonsteroidal anti-inflammatory drug-induced apoptosis', Journal of Biological Chemistry, vol. 280, no. 35, pp. 31059-31067. https://doi.org/10.1074/jbc.M502956200
Tanaka, Ken Ichiro ; Tomisato, Wataru ; Hoshino, Tatsuya ; Ishihara, Tomoaki ; Namba, Takushi ; Aburaya, Mayuko ; Katsu, Takashi ; Suzuki, Keitarou ; Tsutsumi, Shinji ; Mizushima, Tohru. / Involvement of intracellular Ca2+ levels in nonsteroidal anti-inflammatory drug-induced apoptosis. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 35. pp. 31059-31067.
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