Amado Nathália G, Predes Danilo, Fonseca Barbara F, Cerqueira Débora M, Reis Alice H, Dudenhoeffer Ana C, Borges Helena L, Mendes Fábio A, Abreu Jose G
From the Program of Cell and Developmental Biology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21949-590, Brazil.
From the Program of Cell and Developmental Biology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21949-590, Brazil
J Biol Chem. 2014 Dec 19;289(51):35456-67. doi: 10.1074/jbc.M114.621599. Epub 2014 Oct 30.
Flavonoids are plant-derived polyphenolic molecules that have potential biological effects including anti-oxidative, anti-inflammatory, anti-viral, and anti-tumoral effects. These effects are related to the ability of flavonoids to modulate signaling pathways, such as the canonical Wnt signaling pathway. This pathway controls many aspects of embryonic development and tissue maintenance and has been found to be deregulated in a range of human cancers. We performed several in vivo assays in Xenopus embryos, a functional model of canonical Wnt signaling studies, and also used in vitro models, to investigate whether isoquercitrin affects Wnt/β-catenin signaling. Our data provide strong support for an inhibitory effect of isoquercitrin on Wnt/β-catenin, where the flavonoid acts downstream of β-catenin translocation to the nuclei. Isoquercitrin affects Xenopus axis establishment, reverses double axes and the LiCl hyperdorsalization phenotype, and reduces Xnr3 expression. In addition, this flavonoid shows anti-tumoral effects on colon cancer cells (SW480, DLD-1, and HCT116), whereas exerting no significant effect on non-tumor colon cell (IEC-18), suggesting a specific effect in tumor cells in vitro. Taken together, our data indicate that isoquercitrin is an inhibitor of Wnt/β-catenin and should be further investigated as a potential novel anti-tumoral agent.
黄酮类化合物是源自植物的多酚分子，具有潜在的生物学效应，包括抗氧化、抗炎、抗病毒和抗肿瘤作用。这些效应与黄酮类化合物调节信号通路的能力有关，例如经典的Wnt信号通路。该通路控制胚胎发育和组织维持的许多方面，并且已发现在一系列人类癌症中失调。我们在非洲爪蟾胚胎（经典Wnt信号研究的功能模型）中进行了多项体内试验，还使用了体外模型，以研究异槲皮苷是否影响Wnt/β-连环蛋白信号传导。我们的数据为异槲皮苷对Wnt/β-连环蛋白的抑制作用提供了有力支持，其中该黄酮类化合物在β-连环蛋白转运至细胞核的下游起作用。异槲皮苷影响非洲爪蟾轴的建立，逆转双轴和LiCl过度背化表型，并降低Xnr3表达。此外，这种黄酮类化合物对结肠癌细胞（SW480、DLD-1和HCT116）显示出抗肿瘤作用，而对非肿瘤结肠细胞（IEC-18）没有显著影响，表明在体外对肿瘤细胞有特异性作用。综上所述，我们的数据表明异槲皮苷是Wnt/β-连环蛋白的抑制剂，应作为一种潜在的新型抗肿瘤药物进一步研究。
