Moon Yuseok, Yang Hyun, Kim Yung Bu
Department of Microbiology and Immunology and Medical Research Institute, Pusan National University School of Medicine, Busan, 602-739, Republic of Korea.
Toxicol Appl Pharmacol. 2007 Sep 1;223(2):155-63. doi: 10.1016/j.taap.2007.04.018. Epub 2007 May 21.
Non-steroidal anti-inflammatory drugs (NSAIDs) are used to relieve pain and inflammation and have also received considerable attention because of their preventive effects against human cancer. However, the drug application is sometimes limited by the severe gastrointestinal ulcers and mucosal complications. In the present study, NSAID sulindac sulfide was investigated for the cytotoxic injury in the intestinal epithelial cells in association with an immediate inducible factor, early growth response gene 1 (EGR-1). Previously we reported that sulindac sulfide can suppress tumor cell invasion by inducing EGR-1. Extending the previous study, EGR-1 induction by sulindac sulfide was observed both in the non-transformed and transformed human intestinal epithelial cell lines. In terms of signaling pathway, ERK1/2 MAP kinases and its substrate Elk-1 transcription factor were involved in the sulindac sulfide-induced EGR-1 gene expression. Moreover, sulindac sulfide stimulated the nuclear translocation of the transcription factor EGR-1, which was also mediated by ERK1/2 signaling pathway. The roles of EGR-1 signals in the apoptotic cell death were assessed in the intestinal epithelial cells. Suppression of EGR-1 expression retarded cellular growth and colony forming activity in the intestinal epithelial cells. Moreover, induced EGR-1 ameliorated sulindac sulfide-mediated apoptotic cell death and enhanced the cellular survival. Taken all together, sulindac sulfide activated ERK1/2 MAP kinases which then mediated EGR-1 induction and nuclear translocation, all of which played important roles in the cellular survival from NSAID-mediated cytotoxicity in the human intestinal epithelial cells, implicating the protective roles of EGR-1 in the NSAID-mediated mucosal injuries.
非甾体抗炎药（NSAIDs）用于缓解疼痛和炎症，并且因其对人类癌症的预防作用也受到了广泛关注。然而，药物应用有时会受到严重胃肠道溃疡和黏膜并发症的限制。在本研究中，我们研究了NSAID舒林酸硫化物对肠上皮细胞的细胞毒性损伤，并与一种即时诱导因子——早期生长反应基因1（EGR-1）相关联。此前我们报道舒林酸硫化物可通过诱导EGR-1来抑制肿瘤细胞侵袭。在先前研究的基础上，在未转化和转化的人肠上皮细胞系中均观察到舒林酸硫化物诱导EGR-1。在信号通路方面，ERK1/2丝裂原活化蛋白激酶及其底物Elk-1转录因子参与了舒林酸硫化物诱导的EGR-1基因表达。此外，舒林酸硫化物刺激转录因子EGR-1的核转位，这也由ERK1/2信号通路介导。我们在肠上皮细胞中评估了EGR-1信号在凋亡性细胞死亡中的作用。抑制EGR-1表达会阻碍肠上皮细胞的细胞生长和集落形成活性。此外，诱导的EGR-1可改善舒林酸硫化物介导的凋亡性细胞死亡并提高细胞存活率。综上所述，舒林酸硫化物激活ERK1/2丝裂原活化蛋白激酶，进而介导EGR-1的诱导和核转位，所有这些在人肠上皮细胞中NSAID介导的细胞毒性作用下的细胞存活中都发挥了重要作用，这表明EGR-1在NSAID介导的黏膜损伤中具有保护作用。
