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.