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.