title: Embelin reduces colitis-associated tumorigenesis through limiting IL-6/STAT3 signaling.
abstract: 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.
authors.affiliation: Authors' Affiliations: Departments of Gastroenterology, Gerontology, and Pathology, Peking University First Hospital, Beijing; Research Center of Basic Medical Sciences and Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China; and Storr Liver Unit, Westmead Millennium Institute, the University of Sydney at the Westmead Hospital, Westmead, New South Wales, Australia.
authors.forename: Yun
authors.initials: Y
authors.lastname: Dai
authors.forename: Hongmei
authors.initials: H
authors.lastname: Jiao
authors.forename: Guigen
authors.initials: G
authors.lastname: Teng
authors.forename: Weihong
authors.initials: W
authors.lastname: Wang
authors.forename: Rongxin
authors.initials: R
authors.lastname: Zhang
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Wang
authors.forename: Lionel
authors.initials: L
authors.lastname: Hebbard
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.forename: Liang
authors.initials: L
authors.lastname: Qiao
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000209:etiology* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D045325:HCT116 Cells; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016227:Benzoquinones; D016207:Cytokines; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; C010945:embelin