Vitamin D and Wnt signalling in colon cancer
Wnt/β-catenin signalling pathway is abnormally activated in most colorectal adenomas and tumours. Wnt factors are secreted glycoproteins that upon binding to their heterodimeric membrane receptors trigger a signal transduction pathway that leads to the accumulation of β-catenin in the cytosol and its nuclear translocation. Within the cell nucleus, β-catenin regulates a vast number of genes involved in cell proliferation and invasiveness via binding to members of the TCF (T-cell factor) family of transcription factors. In human colorectal cancer, this pathway is activated due to mutation in APC or AXIN1 tumour suppressor genes, or in CTNNB1/β-catenin.
1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), the most active vitamin D3 metabolite, inhibits proliferation and induces differentiation of human colon cancer cells. Our results show that 1,25(OH)2D3 antagonizes Wnt/β-catenin signaling by at least three mechanisms: i) the induction of direct binding between vitamin D receptor and β-catenin, which inhibits formation of transcriptionally active β-catenin/TCF complexes; ii) the upregulation of CDH1/E-cadherin, which leads to the relocation of β-catenin from the nucleus to the plasma membrane; and iii) the induction of the DKK-1 gene, which encodes an extracellular inhibitor of Wnt proteins.
DKK-1 is silenced in 25% of advanced colorectal tumours due to promoter methylation, which implies the loss of this negative control of the Wnt/β-catenin pathway. Moreover, ectopic expression of DKK-1 in non-expressing DLD-1 cells reduced cell proliferation in vitro and tumour formation in immunodeficient mice. DLD-1 cells bear a truncated APC gene and so, they have a constitutively active Wnt/β-catenin pathway. Together with data in other cell types, this suggests that DKK-1 has antitumoural effects that are independent of the antagonism of Wnt signalling at the plasma membrane and of β-catenin/TCF transcriptional activity. In summary, our results indicate that the antagonism of the Wnt/β-catenin signalling is relevant for the complex antineoplastic activity of 1,25(OH)2D3.