Namba Takushi, Homan Takashi, Nishimura Tomoko, Mima Shinji, Hoshino Tatsuya, Mizushima Tohru
Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
J Biol Chem. 2009 Feb 13;284(7):4158-67. doi: 10.1074/jbc.M806051200. Epub 2008 Dec 10.
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.
流行病学研究表明，长期使用非甾体抗炎药（NSAIDs）可降低患癌风险。多种机制，包括诱导细胞凋亡以及抑制癌细胞的生长和侵袭，都与这种抗肿瘤活性有关。在本研究中，我们聚焦于S100P，已知其在临床分离的肿瘤中过度表达，且通过细胞内和细胞外机制发挥作用。我们发现，用包括塞来昔布在内的多种NSAIDs处理人胃癌细胞后，S100P表达上调。用针对激活转录因子4（ATF4）的小干扰RNA转染细胞可抑制塞来昔布介导的S100P上调，ATF4是一种参与内质网应激反应的转录因子。此外，缺失位于S100P基因启动子中的ATF4结合共有序列会导致塞来昔布介导的该基因转录激活受到抑制。这些结果表明，塞来昔布通过ATF4介导的内质网应激反应上调S100P的表达。塞来昔布抑制细胞生长并诱导细胞凋亡，用S100P过表达质粒或小干扰RNA分别转染细胞可抑制或促进这些作用。塞来昔布还抑制细胞的侵袭活性。色甘酸钠可抑制S100P与其受体的结合，增强塞来昔布介导的对细胞侵袭和生长的抑制作用，但不影响细胞凋亡。这些结果表明，S100P通过细胞内或细胞外机制影响细胞凋亡、细胞生长和侵袭，且NSAIDs上调S100P表达会降低其抗肿瘤活性。
