Dietary cocoa inhibits colitis associated cancer: a crucial involvement of the IL-6/STAT3 pathway.
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.
Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
Zeinab
Z
Saadatdoust
Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia; Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. Electronic address: panduashokkumar@gmail.com.
Ashok Kumar
AK
Pandurangan
Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia; Department of Biochemistry, Central Leather Research Institute, Council of Scientific and Industrial Research (CSIR), Adyar, Chennai 600 020, India.
Suresh Kumar
SK
Ananda Sadagopan
Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia; Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia. Electronic address: nhaizan@upm.edu.my.
Norhaizan
N
Mohd Esa
Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
Amin
A
Ismail
Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Mohd Rais
MR
Mustafa
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry; D000975:Antioxidants / Q000737:chemistry; D017209:Apoptosis; D001397:Azoxymethane / Q000737:chemistry; D002099:Cacao / Q000737:chemistry*; D053148:Caspase 3 / Q000378:metabolism; D003092:Colitis / Q000150:complications / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D016264:Dextran Sulfate / Q000737:chemistry; D004032:Diet; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D059808:Polyphenols / Q000737:chemistry; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D000975:Antioxidants; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D015850:Interleukin-6; D059808:Polyphenols; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D016264:Dextran Sulfate; D009195:Peroxidase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D001397:Azoxymethane
Apoptosis; Cocoa; Colitis associated cancer; IL-6; NF-κB; STAT3