|Wang, Dan -|
|Li, Feng -|
|Dey, Moul -|
Submitted to: PLoS One
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 22, 2012
Publication Date: December 16, 2012
Citation: Wang, D., Wise, M.L., Li, F., Dey, M. 2012. Phytochemicals attenuating aberrant activation of ß-catenin in cancer cells. PLoS One. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0050508. Interpretive Summary: A group of phytochemicals, including avenanthramides from oat, were analyzed for their ability to inhibit the Wnt signaling pathway, a mammalian cell regulation pathway important in embryonic development and cellular differentiation. An intracellular component of the Wnt pathway is ß-catenin, a transcription factor responsible for transmitting the extracellular Wnt signal into the cell nucleus. Over activation of this pathway is strongly associated with development of several cancers, including cervical and colorectal cancer. In this study of five natural products, triptolide proved to be the most effective inhibitor, reducing the level of ß-catenin activation by 80% when tested in the nanomolar concentration range. Avenanthramide 2p also proved to be an effective inhibitor when assayed in the micromolar range. The impact of this study is to present the potential for dietary intervention in the development of these cancer lines.
Technical Abstract: Phytochemicals are a rich source of chemoprevention agents but their effects on modulating the Wnt/ß-catenin signaling pathway have remained largely uninvestigated. Aberrantly activated Wnt signaling can result in the abnormal stabilization of ß-catenin, a key causative step in a broad spectrum of cancers. Here we report the modulation of lithium chloride-activated canonical Wnt/ ß-catenin signaling by phytochemicals that have antioxidant, anti-inflammatory or chemopreventive properties. The compounds were first screened with a cervical cancer-derived stable Wnt signaling reporter HeLa cell line. Positive hits were subsequently evaluated for ß-catenin degradation, suppression of ß-catenin nuclear localization and down-regulation of downstream oncogenic targets of the Wnt/ß-catenin pathway. Our study shows novel degradation of the ß-catenin protein in HeLa cells by avenanthramide 2p (a polyphenol) and triptolide (a diterpene triepoxide) from oats and a Chinese medicinal plant respectively. The findings present avenanthramide 2p as a potential chemopreventive dietary compound that merits further study using in vivo models of cancers; they also provide a new perspective on the molecular mechanisms of Triptolide biological activity. The findings present avenanthramide 2p as a potential chemopreventive dietary compound that merits further study using in vivo models of cancers; they also provide a new perspective on the molecular mechanisms of triptolide biological activity.