Embelin Reduces Colitis-Associated Tumorigenesis through Limiting IL-6/STAT3 Signaling
Embelin Reduces Colitis-Associated Tumorigenesis through Limiting IL-6/STAT3 Signaling
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Embelin 通过限制 IL-6/STAT3 信号传导减少结肠炎相关的肿瘤发生
DOI：
10.1158/1535-7163.mct-13-0378
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发表时间：
2014-05-01
影响因子：
5.7
通讯作者：
Qiao, Liang
中科院分区：
文献类型：
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作者：
Dai, Yun;Jiao, Hongmei;Qiao, Liang
白介素6(IL-6)/STAT3信号调节肠上皮细胞的存活和增殖，在炎症性肠病和结直肠癌的发病机制中起重要作用。Embelin是X连锁凋亡抑制蛋白(XIAP)的小分子抑制剂，具有抗氧化、抗炎、抗肿瘤等活性。我们先前的研究表明恩贝林在体外抑制结肠癌细胞的生长，并有效地抑制1，2-二甲基肼二盐酸盐诱导的小鼠结肠癌的发生。在此，我们利用偶氮甲烷/葡聚糖硫酸钠(AOM/DSS)模型探讨了恩贝林对结肠炎相关癌(CAC)的抗肿瘤作用及其机制，重点探讨了恩贝林是否通过IL-6/STAT3途径发挥作用。我们发现恩贝林显著降低了CAC荷瘤小鼠的发病率和肿瘤大小。除了抑制肿瘤上皮细胞的增殖外，Embelin还在体内抑制结肠IL-6的表达和分泌，并随后抑制STAT3的激活。重要的是，体外研究表明，在结肠癌细胞中，Embelin通过刺激含有Src同源结构域2的蛋白酪氨酸磷酸酶(SHP2)的活性来降低结构性和IL-6诱导的STAT3的激活。此外，Embelin在肿瘤发生前保护小鼠免受AOM/DSS诱导的结肠炎。恩贝林降低IL-1β、IL-17a和IL-23a的表达，减少结肠组织中T细胞和巨噬细胞的数量。因此，我们的研究结果表明，Embelin抑制CAC的发生，其抗肿瘤作用部分是通过抑制IL-6/STAT3的激活和Th17免疫反应来实现的。恩贝林可能是预防和治疗CAC的潜在药物。摩尔癌症治疗；13(5)；1206-16。
The interleukin-6 (IL-6)/STAT3 signaling regulates survival and proliferation of intestinal epithelial cells and plays an important role in the pathogenesis of inflammatory bowel disease and colorectal cancer. Embelin is a small molecule inhibitor of X-linked inhibitor of apoptosis protein (XIAP), with antioxidant, anti-inflammatory, and antitumor activities. We previously showed that embelin inhibits the growth of colon cancer cells in vitro, and effectively suppresses 1,2-dimethylhydrazine dihydrochloride-induced colon carcinogenesis in mice. Here, we explored the antitumor effects and mechanisms of embelin on colitis-associated cancer (CAC) using the azoxymethane/dextran sulfate sodium (AOM/DSS) model, with a particular focus on whether embelin exerts its effect through the IL-6/STAT3 pathway. We found that embelin significantly reduced incidence and tumor size in CAC-bearing mice. In addition to inhibiting proliferation of tumor epithelial cells, embelin suppressed colonic IL-6 expression and secretion, and subsequently STAT3 activation in vivo. Importantly, in vitro studies have revealed that in colon cancer cells, embelin diminished both the constitutive and IL-6–induced STAT3 activation by stimulating Src homology domain 2-containing protein tyrosine phosphatase (SHP2) activity. Moreover, embelin protected mice from AOM/DSS-induced colitis before tumor development. Embelin decreased IL-1β, IL-17a, and IL-23a expression as well as the number of CD4+ T cells and macrophages infiltrating the colonic tissues. Thus, our findings demonstrated that embelin suppresses CAC tumorigenesis, and its antitumor effect is partly mediated by limiting IL-6/STAT3 activation and Th17 immune response. Embelin may be a potential agent in the prevention and treatment of CAC. Mol Cancer Ther; 13(5); 1206–16. ©2014 AACR.