Abstract
Canonical Wnt signaling is deregulated in several types of human cancer where it plays a central role in tumor cell growth and progression. Here we report the identification of 2 new small molecules that specifically inhibit canonical Wnt pathway at the level of the destruction complex. Specificity was verified in various cellular reporter systems, a Xenopus double-axis formation assay and a gene expression profile analysis. In human colorectal cancer (CRC) cells, the new compounds JW67 and JW74 rapidly reduced active β-catenin with a subsequent downregulation of Wnt target genes, including AXIN2, SP5, and NKD1. Notably, AXIN2 protein levels were strongly increased after compound exposure. Long-term treatment with JW74 inhibited the growth of tumor cells in both a mouse xenograft model of CRC and in Apc(Min) mice (multiple intestinal neoplasia, Min). Our findings rationalize further preclinical and clinical evaluation of these new compounds as novel modalities for cancer treatment.
Highlights
Introduction bCatenin is a key component of the Wnt pathway that upon Wnt activation translocates to the nucleus where it activates gene transcription in association with TCF/LEF transcription factors
2 chemotypes, JW67 and JW74, were identified that inhibit canonical Wnt signaling, decreased Wnt-dependent transcription in colorectal cancer (CRC) cell lines that resulted in a reduced cell growth in vitro and in vivo, and inhibited polyp formation in ApcMin mice
A detailed mechanism of action will be investigated in further studies, the inhibitory effect of JW67 and JW74 in LiCl-activated cells and in adenomatous polyposis coli (APC) mutant cells indicates that the compounds may influence the multiprotein complex consisting of b-catenin/GSK-3b/AXIN/APC /CK1 that controls the degradation of b-catenin
Summary
Catenin is a key component of the Wnt pathway that upon Wnt activation translocates to the nucleus where it activates gene transcription in association with TCF/LEF transcription factors. Canonical Wnt signaling plays a crucial role in embryonic development, and in a deregulated stage, Wnt signaling is a common denominator in a variety of tumors [1,2,3]. About 90% of sporadic colon cancers show aberrant Wnt signaling [2, 4, 5], whereas all pancreatic adenocarcinomas exhibit alterations in Wnt/Notch signaling [6]. Mutations in the adenomatous polyposis coli (APC), b-catenin, or AXIN genes lead to the accumulation of nuclear b-catenin and contribute to tumor initiation and progression [5]. Alterations in extracellular proteins that silence Wnt signaling, including secreted frizzled related proteins [7], Dickkopf (DKK; ref. 8), and members of the Wnt inhibitor factor (WIF) family [9], may lead to an abnormal pathway activity [10]
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