Abstract
The Wnt/β-catenin signaling pathway is important for tumor initiation and progression. The low density lipoprotein receptor-related protein-6 (LRP6) is an essential Wnt co-receptor for Wnt/β-catenin signaling and represents a promising anticancer target. Recently, the antihelminthic drug, niclosamide was found to inhibit Wnt/β-catenin signaling, although the mechanism was not well defined. We found that niclosamide was able to suppress LRP6 expression and phosphorylation, block Wnt3A-induced β-catenin accumulation, and inhibit Wnt/β-catenin signaling in HEK293 cells. Furthermore, the inhibitory effects of niclosamide on LRP6 expression/phosphorylation and Wnt/β-catenin signaling were conformed in human prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. Moreover, we showed that the mechanism by which niclosamide suppressed LRP6 resulted from increased degradation as evident by a shorter half-life. Finally, we demonstrated that niclosamide was able to induce cancer cell apoptosis, and displayed excellent anticancer activity with IC50 values less than 1 µM for prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. The IC50 values are comparable to those shown to suppress the activities of Wnt/β-catenin signaling in prostate and breast cancer cells. Our data indicate that niclosamide is a unique small molecule Wnt/β-catenin signaling inhibitor targeting the Wnt co-receptor LRP6 on the cell surface, and that niclosamide has a potential to be developed a novel chemopreventive or therapeutic agent for human prostate and breast cancer.
Highlights
Wnt/b-catenin signaling plays an important role in embryonic development and can lead to tumor formation when aberrantly activated
We demonstrated for the first time that niclosamide can inhibit Wnt/b-catenin signaling by inducing lipoprotein receptor-related protein-6 (LRP6) degradation, and that this activity is closely associated with its antiproliferative and apoptosis inducing activity
Given that niclosamide can block Wnt/b-catenin signaling in cancer cells and can induce apoptosis, we examined the effect of niclosamide on cancer cell proliferation
Summary
Wnt/b-catenin signaling plays an important role in embryonic development and can lead to tumor formation when aberrantly activated. In the absence of Wnt ligands, b-catenin levels are efficiently regulated by a supramolecular complex containing adenomatous polyposis coli (APC), axin, and glycogen synthetase kinase 3b (GSK3b). This complex promotes phosphorylation of b-catenin by casein kinase 1 (Ck1) and GSK3b. Phosphorylated b-catenin becomes multi-ubiquitinated (Ub) and degraded by the 26S proteasome The action of this complex is inhibited upon the binding of Wnt to its receptors on the cell surface [1,2]. A variety of Wnt/b-catenin target genes have been identified, including those that regulate cell proliferation and apoptosis, mediating cancer initiation and progression [3,4,5]. Compelling evidence has indicated that there is an abnormal up-regulation of this pathway in tumorigenesis of many types of cancer, and that disruption of
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