title: Ellagic acid coordinately attenuates Wnt/β-catenin and NF-κB signaling pathways to induce intrinsic apoptosis in an animal model of oral oncogenesis.
abstract: OBJECTIVE
  Constitutive activation of the Wnt signaling pathway and its downstream effectors plays a key role in neoplastic transformation. The objective of this study was to investigate the effect of ellagic acid, a plant-derived polyphenol on Wnt/β-catenin signaling and its downstream circuits- NF-κB and mitochondrial apoptosis in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model.
  
  
  METHODS
  Hamsters were divided into six groups. The right buccal pouches of animals in groups 1-4 were painted with 0.5% DMBA three times a week for 14 weeks. Animals in groups 2-4 received in addition basal diet containing ellagic acid at a concentration of 0.1, 0.2, and 0.4% in the diet. Group 5 animals were given 0.4% ellagic acid alone. Group 6 animals served as control. The expression of the members of Wnt and NF-κB signaling and intrinsic apoptosis was evaluated by western blot analysis.
  
  
  RESULTS
  Dietary supplementation of 0.4% ellagic acid suppressed the development of HBP carcinomas by preventing the constitutive activation of Wnt pathway through the downregulation of Fz, Dvl-2, GSK-3β and nuclear translocation of β-catenin. Abrogation of Wnt signaling by ellagic acid was also associated with inactivation of NF-κB and modulation of key components of the mitochondrial apoptotic network.
  
  
  CONCLUSIONS
  Our findings suggest a functional crosstalk between Wnt and NF-κB signaling pathways in HBP carcinomas that is blocked by ellagic acid supplementation. Dietary ellagic acid that targets the Wnt/β-catenin pathway as well as its downstream signaling mediators is a unique candidate for cancer chemoprevention.
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Chidambaram, Tamil Nadu, 608 002, India.
authors.forename: Prabukumar
authors.initials: P
authors.lastname: Anitha
authors.forename: Ramamurthi Vidya
authors.initials: RV
authors.lastname: Priyadarsini
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Kavitha
authors.forename: Paranthaman
authors.initials: P
authors.lastname: Thiyagarajan
authors.forename: Siddavaram
authors.initials: S
authors.lastname: Nagini
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002610:Cheek / Q000473:pathology; D006224:Cricetinae; D004195:Disease Models, Animal; D015536:Down-Regulation; D004610:Ellagic Acid / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D009061:Mouth Mucosa / Q000473:pathology; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D010936:Plant Extracts; D051176:beta Catenin; D004610:Ellagic Acid; D015127:9,10-Dimethyl-1,2-benzanthracene; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3