Embelin reduces colitis-associated tumorigenesis through limiting IL-6/STAT3 signaling

Dai, Yun, Jiao, Hongmei, Teng, Guigen, Wang, Weihong, Zhang, Rongxin, Wang, Yunhong, Hebbard, Lionel, George, Jacob, and Qiao, Liang (2014) Embelin reduces colitis-associated tumorigenesis through limiting IL-6/STAT3 signaling. Molecular Cancer Therapeutics, 13 (5). pp. 1206-1216.

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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.

Item ID: 40183
Item Type: Article (Research - C1)
ISSN: 1538-8514
Funders: National Natural Science Foundation of China (NSFC), Natural Science Foundation of Beijing (NSFB), Ministry of Science and Technology of China (MSTC), Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney, National Health and Medical Research Council of Australia (NHMRC)., Cancer Council NSW (CC), Cancer Institute NSW (CI)
Projects and Grants: NSFC #81072019, NSFB 7122189, NSFC #81172271, MSTC #2012CB932503, MSTC #2011CB933100, NSFC #91029705, NHMRC Program Grant 1053206, Project Grant APP1047417, CC grant APP1070076, CC grant APP1069733, CI Career Development and Support Fellowship Future Research Leader Grant 08/FRL/1-04
Date Deposited: 26 Aug 2015 23:46
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1112 Oncology and Carcinogenesis > 111201 Cancer Cell Biology @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920102 Cancer and Related Disorders @ 100%
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