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J. Biol. Chem., Vol. 280, Issue 35, 31059-31067, September 2, 2005

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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, and Tohru Mizushima¶

From the Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, and the Faculty of Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan

We recently reported that nonsteroidal anti-inflammatory drug (NSAID)-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. An 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.

Received for publication, March 17, 2005 , and in revised form, May 25, 2005.

^* This work was supported by grants-in-aid for scientific research from the Ministry of Health, Labour, and Welfare of Japan as well as by the Suzuken Memorial Foundation, the Tokyo Biochemical Research Foundation, the Kumamoto Technology and Industry Foundation, and the Japan Research Foundation for Clinical Pharmacology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan. Tel./Fax: 81-96-371-4323; E-mail: mizu{at}gpo.kumamoto-u.ac.jp.

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