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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Tanaka, K. I., 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, 280(35), 31059-31067. https://doi.org/10.1074/jbc.M502956200