Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Chidambaram, Tamil Nadu, 608 002, India.
Eur J Nutr. 2013 Feb;52(1):75-84. doi: 10.1007/s00394-011-0288-y. Epub 2011 Dec 11.
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.
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.
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.
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.
Wnt 信号通路及其下游效应物的组成性激活在肿瘤转化中起着关键作用。本研究旨在探讨鞣花酸（一种植物来源的多酚）对 7,12-二甲基苯并[a]蒽（DMBA）诱导的颊囊（HBP）致癌模型中 Wnt/β-连环蛋白信号及其下游通路-NF-κB 和线粒体凋亡的影响。
将仓鼠分为六组。第 1-4 组动物的右侧颊囊每周涂抹 0.5%DMBA 三次，共 14 周。第 2-4 组动物同时给予基础饮食，饮食中鞣花酸浓度分别为 0.1%、0.2%和 0.4%。第 5 组动物单独给予 0.4%鞣花酸。第 6 组动物作为对照。通过 Western blot 分析评估 Wnt 和 NF-κB 信号及内在凋亡成员的表达。
膳食补充 0.4%鞣花酸可通过下调 Fz、Dvl-2、GSK-3β 和核内 β-连环蛋白转位来抑制 HBP 癌的发生，从而抑制 Wnt 通路的组成性激活。鞣花酸对 Wnt 信号的阻断也与 NF-κB 的失活和线粒体凋亡网络关键成分的调节有关。
我们的研究结果表明，在 HBP 癌中存在 Wnt 和 NF-κB 信号通路之间的功能串扰，而鞣花酸的补充可阻断这种串扰。针对 Wnt/β-连环蛋白通路及其下游信号转导介质的膳食鞣花酸是癌症化学预防的独特候选药物。
