WAY-262611 ameliorates the inflammatory bowel disease by activating Wnt/β-catenin pathway

Abstract

Inflammatory bowel disease (IBD) is a non-specific and relapsing intestinal inflammation. The injury and repair of intestinal epithelial together determine the occurrence and development of IBD. Wnt/β-catenin pathway is considered as the key role in the proliferation and differentiation of intestinal stem cells which is negative regulated by Dickkiop (DKKs). WAY-262611 is a novel inhibitor of DKK-1, and has demonstrated therapeutic effect on some disease including osteoporosis. Thus, we investigated the effect of WAY-262611 on IBD. Firstly, a mice model of IBD was established by DSS induction, by which the expression of Wnt3a and DKK-1 were detected by immumohistochemical staining to display their correlation. Next, using WAY-262611 the ameliorative effect on IBD was validated by histopathological staining. Using Mode-k cells the experiments in vitro were also conducted, in which the viability and apoptosis were determined. By detecting expression of Wnt3a and DKK-1 and observing nuclear translocation of β-catenin, the activation of Wnt/β-catenin pathway was validated. Finally, the incidence of the orthotopic colorectal cancer was calculated under continuous administration by DSS. Results demonstrated that the expression of Wnt3a is negative correlated with DKK-1. WAY-262611 ameliorated the IBD and reduced apoptosis of Mode-k cells induced by DSS. The protective effect of WAY-262611 on Mode-k cells is mediated by Wnt/β-catenin pathway activation. In addition, WAY-262611 lowered the incidence rate of orthotopic colorectal cancer. All these results concluded that WAY-262611 could mitigate the IBD by activating Wnt/β-catenin pathway in mice.

Keywords: DKK-1 inhibitor; Inflammatory bowel disease; WAY-262611; Wnt/β-catenin.