Up-regulation of S100P expression by non-steroidal anti-inflammatory drugs and its role in anti-tumorigenic effects.
Epidemiological studies have revealed that prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of cancer. Various mechanisms, including induction of apoptosis and inhibition of the growth and invasion of cancer cells, have been implicated in this anti-tumorigenic activity. In this study we focused on S100P, which is known to be overexpressed in clinically isolated tumors and which functions through both intracellular and extracellular mechanisms. We showed the up-regulation of S100P expression in human gastric carcinoma cells treated with various NSAIDs, including celecoxib. The celecoxib-mediated up-regulation of S100P was suppressed by the transfection of cells with small interfering RNA for activating transcription factor 4 (ATF4), a transcription factor involved in the endoplasmic reticulum stress response. Furthermore, deletion of ATF4 binding consensus sequence located in the promoter of the S100P gene resulted in inhibition of celecoxibmediated transcriptional activation of the gene. These results suggest that celecoxib up-regulates the expression of S100P through an ATF4-mediated endoplasmic reticulum stress response. Celecoxib inhibited the growth and induced apoptosis, and these actions could be either suppressed or stimulated by transfection of cells with S100P overexpression plasmid or small interfering RNA, respectively. Celecoxib also inhibited the invasive activity of the cells. Cromolyn, which inhibits the binding of S100P to its receptor, enhanced the celecoxib-mediated inhibition of cell invasion and growth but did not affect apoptosis. These results suggest that S100P affects apoptosis, cell growth, and invasion through either an intracellular or an extracellular mechanism and that the up-regulation of S100P expression by NSAIDs reduces their anti-tumorigenic activity.
Namba
Takushi
T
Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Homan
Takashi
T
Nishimura
Tomoko
T
Mima
Shinji
S
Hoshino
Tatsuya
T
Mizushima
Tohru
T
D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002135:Calcium-Binding Proteins / Q000096:biosynthesis*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D016384:Consensus Sequence; D004205:Cromolyn Sodium / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D011720:Pyrazoles / Q000494:pharmacology; D020218:Response Elements; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
C497109:ATF4 protein, human; D018927:Anti-Asthmatic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002135:Calcium-Binding Proteins; D009363:Neoplasm Proteins; D011720:Pyrazoles; C103003:S100P protein, human; D013449:Sulfonamides; D051701:Activating Transcription Factor 4; D000068579:Celecoxib; D004205:Cromolyn Sodium