Embelin Reduces Colitis-Associated Tumorigenesis through Limiting IL-6/STAT3 Signaling

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-1 beta, 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. (C) 2014 AACR.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000335961600016&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701OncologySCI(E)PubMed15ARTICLEdaiyun1@medmail.com.cn; qlia8530@usyd.edu.au51206-12161