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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.
AuthorsYun Dai, Hongmei Jiao, Guigen Teng, Weihong Wang, Rongxin Zhang, Yunhong Wang, Lionel Hebbard, Jacob George, Liang Qiao
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 5 Pg. 1206-16 (May 2014) ISSN: 1538-8514 [Electronic] United States
PMID24651526 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzoquinones
  • Cytokines
  • Interleukin-6
  • STAT3 Transcription Factor
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ptpn11 protein, mouse
  • embelin
Topics
  • Animals
  • Benzoquinones (pharmacology)
  • CD4-Positive T-Lymphocytes (immunology, metabolism, pathology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cell Transformation, Neoplastic (drug effects, metabolism)
  • Colitis (chemically induced, complications, metabolism)
  • Colonic Neoplasms (etiology, pathology)
  • Cytokines (genetics, metabolism)
  • Disease Models, Animal
  • HCT116 Cells
  • Humans
  • Interleukin-6 (genetics, metabolism)
  • Macrophages (immunology, metabolism, pathology)
  • Male
  • Mice
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 (metabolism)
  • STAT3 Transcription Factor (metabolism)
  • Signal Transduction (drug effects)

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