Common Food Additive Carrageenan Stimulates Wnt/ β-Catenin Signaling in Colonic Epithelium by Inhibition of Nucleoredoxin Reduction

Abstract

Exposure to the common food additive carrageenan was previously associated with increased Wnt9A expression and increased cytoplasmic β-catenin in human colonic epithelial cells. In this report, exposure of human colonic epithelial cells in culture and of mouse colonic epithelium in vivo to low concentrations of carrageenan is shown to activate the Wnt/β-catenin signaling pathway, leading to increases in nuclear β-catenin, T-cell factor/lymphoid enhancer factor activation, and cyclin D1 expression and decline in bone morphogenetic protein-4. These effects are mediated through carrageenan-induced reactive oxygen species (ROS), and inhibited by the ROS scavenger Tempol. Carrageenan exposure and ROS production inhibited thioredoxin reductase activity and increased oxidation of nucleoredoxin, a member of the thioredoxin family of redox proteins. When oxidized, nucleoredoxin co-immunoprecipitation with dishevelled (DVL) declined, enabling DVL to interact with and inhibit the cytoplasmic β-catenin destruction complex, and facilitating nuclear translocation of β-catenin. Both nucleoredoxin silencing and carrageenan exposure produced similar declines in thioredoxin reductase activity. In addition to activation of Wnt signaling, carrageenan exposure also increased Wnt9A mRNA expression in the mouse colonic epithelium and the human colonic epithelial cells, thereby potentially permitting ongoing stimulation of the Wnt/β-catenin pathway. These findings suggest how a common dietary ingredient can contribute to colon carcinogenesis by effects on Wnt signaling and Wnt expression.