Dietary cocoa inhibits colitis associated cancer: a crucial involvement of the IL-6/STAT3 pathway

J Nutr Biochem. 2015 Dec;26(12):1547-58. doi: 10.1016/j.jnutbio.2015.07.024. Epub 2015 Aug 10.

Abstract

Patients with inflammatory bowel disease (IBD) are at increased risk for developing ulcerative colitis-associated colorectal cancer (CRC). The interleukin-6 (IL-6)/signal transducer and activator of transcription (STAT)-3 signaling regulates survival and proliferation of intestinal epithelial cells and play an important role in the pathogenesis of IBD and CRC. Cocoa is enriched with polyphenols that known to possess antioxidant, anti-inflammatory and antitumor activities. Here, we explored the antitumor effects and mechanisms of cocoa diet on colitis-associated cancer (CAC) using the azoxymethane/dextran sulfate sodium model, with a particular focus on whether cocoa exerts its anticancer effect through the IL-6/STAT3 pathway. We found that cocoa significantly decreased the tumor incidence and size in CAC-induced mice. In addition to inhibiting proliferation of tumor epithelial cells, cocoa suppressed colonic IL-6 expression and subsequently activation of STAT3. Thus, our findings demonstrated that cocoa diet suppresses CAC tumorigenesis, and its antitumor effect is partly mediated by limiting IL-6/STAT3 activation. In addition, cocoa induces apoptosis by increased the expressions of Bax and caspase 3 and decreased Bcl-xl. Thus, we conclude that cocoa may be a potential agent in the prevention and treatment of CAC.

Keywords: Apoptosis; Cocoa; Colitis associated cancer; IL-6; NF-κB; STAT3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Antineoplastic Agents / chemistry
  • Antioxidants / chemistry
  • Apoptosis
  • Azoxymethane / chemistry
  • Cacao / chemistry*
  • Caspase 3 / metabolism
  • Colitis / complications
  • Colitis / metabolism
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / prevention & control*
  • Dextran Sulfate / chemistry
  • Diet*
  • Epithelial Cells / metabolism
  • Female
  • Gene Expression Regulation
  • Inflammatory Bowel Diseases / complications
  • Inflammatory Bowel Diseases / metabolism
  • Interleukin-6 / metabolism*
  • Intestinal Mucosa / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Microscopy, Confocal
  • Neoplasms / pathology
  • Peroxidase / metabolism
  • Polyphenols / chemistry
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • bcl-2-Associated X Protein / metabolism
  • bcl-X Protein / metabolism

Substances

  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • Antioxidants
  • Bax protein, mouse
  • Bcl2l1 protein, mouse
  • Interleukin-6
  • Polyphenols
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Dextran Sulfate
  • Peroxidase
  • Casp3 protein, mouse
  • Caspase 3
  • Azoxymethane