Involvement of up-regulation of PUMA in non-steroidal anti-inflammatory drug-induced apoptosis.
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.
Ishihara
Tomoaki
T
Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Hoshino
Tatsuya
T
Namba
Takushi
T
Tanaka
Ken-ichiro
K
Mizushima
Tohru
T
D051701:Activating Transcription Factor 4 / Q000502:physiology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002118:Calcium / Q000378:metabolism; D000068579:Celecoxib; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011720:Pyrazoles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000502:physiology
C497109:ATF4 protein, human; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C497249:DDIT3 protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D034741:RNA, Small Interfering; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D005047:Etoposide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000068579:Celecoxib; D002118:Calcium