Abstract
NSAIDs such as celecoxib induce apoptosis in cancer cells. Although this apoptotic effect is involved in the anti-tumor activity associated with such drugs, the mechanism by which this occurs is not fully understood. We report here that various NSAIDs, including celecoxib, up-regulate PUMA, a Bcl-2 family protein with potent apoptosis-inducing activity, in human gastric carcinoma cell line, accompanying the induction of apoptosis. Experiments using siRNA and an intracellular Ca(2+) chelator revealed that Ca(2+)-dependent up-regulation of ATF4 and CHOP is involved in this up-regulation of PUMA. The siRNA for PUMA inhibited the celecoxib-induced activation and translocation of Bax, release of cytochrome c into the cytosol and induction of apoptosis, suggesting that PUMA plays an important role in celecoxib-induced mitochondrial dysfunction and the resulting apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 4 / physiology
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins / genetics*
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Calcium / metabolism
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Celecoxib
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Cell Line, Tumor
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Cyclooxygenase 2 / genetics
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Etoposide / pharmacology
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Humans
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Membrane Proteins / genetics
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Proto-Oncogene Proteins / genetics*
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Pyrazoles / pharmacology
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RNA, Small Interfering / pharmacology
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Sulfonamides / pharmacology
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Transcription Factor CHOP / physiology
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Tumor Suppressor Protein p53 / physiology
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Up-Regulation
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bcl-2-Associated X Protein / physiology
Substances
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ATF4 protein, human
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Anti-Inflammatory Agents, Non-Steroidal
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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DDIT3 protein, human
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Membrane Proteins
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Proto-Oncogene Proteins
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Pyrazoles
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RNA, Small Interfering
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Sulfonamides
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Tumor Suppressor Protein p53
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bcl-2-Associated X Protein
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Activating Transcription Factor 4
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Transcription Factor CHOP
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Etoposide
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Cyclooxygenase 2
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PTGS2 protein, human
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Celecoxib
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Calcium