Vitamin D Is a Multilevel Repressor of Wnt/b-Catenin Signaling in Cancer Cells

Abstract

The Wnt/b-catenin signaling pathway is abnormally activated in most colorectal cancers and in a proportion of other neoplasias. This activation initiates or contributes to carcinogenesis by regulating the expression of a large number of genes in tumor cells. The active vitamin D metabolite 1a,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits Wnt/b-catenin signaling by several mechanisms at different points along the pathway. Additionally, paracrine actions of 1,25(OH)2D3 on stromal cells may also repress this pathway in neighbouring tumor cells. Here we review the molecular basis for the various mechanisms by which 1,25(OH)2D3 antagonizes Wnt/b-catenin signaling, preferentially in human colon carcinoma cells, and the consequences of this inhibition for the phenotype and proliferation rate. The effect of the vitamin D system on Wnt/b-catenin signaling and tumor growth in animal models will also be commented in detail. Finally, we revise existing data on the relation between vitamin D receptor expression and vitamin D status and the expression of Wnt/b-catenin pathway genes and targets in cancer patients.

Figure 1

Schematic representation of the mechanisms of Wnt/β-catenin pathway repression by 1,25(OH)₂D₃ in human colon carcinoma cells. (a) Wnt/β-catenin pathway is activated by mutation of APC, CTNNB1/β-catenin or AXIN genes, or by deregulated signaling from Wnt plasma membrane receptors. These alterations cause accumulation of β-catenin protein in the cytoplasm and nucleus and transcription of its target genes; (b) 1,25(OH)₂D₃ inhibits β-catenin/TCF transcriptional activity in colon carcinoma cells by several mechanisms. It promotes VDR/β-catenin binding, thus reducing the amount of β-catenin bound to TCF (1); it induces the expression of CDH1 gene coding for E-cadherin, which sequesters β-catenin at the plasma membrane adherens junctions (2); and it enhances the expression of the extracellular Wnt inhibitor DKK-1 (3) and of TCF4 (4). Additional paracrine mechanisms of antagonism have been proposed.