Abstract
Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85% of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes.
Highlights
The WNT-signaling pathway plays a pivotal role in embryonic development, stem cell biology, maintenance of the normal intestinal epithelium, and as a driver of carcinogenesis
In the absence of WNT activity, steady-state levels of the transcriptional activator b-CATENIN (CTNNB1) are reduced by a destruction complex consisting of ADENOMATOUS POLYPOSIS COLI (APC), GLYCOGEN SYNTHASE-KINASE 3b (GSK3b), CASEIN KINASE-1 a (CK1a) and AXIN [1,2,3,4]
Pyrvinium does not have a general toxicity on cell growth, as its ability to attenuate the proliferation of colorectal cancer (CRC) cells lacking APC can be reduced by re-expressing APC [36]
Summary
The WNT-signaling pathway plays a pivotal role in embryonic development, stem cell biology, maintenance of the normal intestinal epithelium, and as a driver of carcinogenesis. Upon WNT activation the destruction complex is disassembled, CTNNB1 is stabilized and accumulates in the nucleus where WNT-target gene expression is elevated leading to proliferation and growth [1,2,3,5]. WNT-pathway activation is a key factor in the etiology and maintenance of colorectal cancer (CRC), with loss of function mutations in the tumor suppressor APC being the main cause [8,9,10]. Truncated APC mutants and degradation resistant CTNNB1 point mutations are found in 80% and 10% of all spontaneous CRC cases respectively [10,11]. In spontaneous CRC, alterations in APC mark the earliest event leading to carcinogenesis whereas mutations in other CRC associated oncogenes including RAS and the tumor suppressor p53 are considered late events [11].
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