Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of β-catenin signaling

• DOI: 10.1083/jcb.200102028
• Publication Date: 2002-07-26T16:47:50Z
• Authors: Héctor G. Pálmer; José Manuel Gonz...; Jesús Espada; María T. Berciano; Isabel Puig; Josep Baulida; Miguel Quintanilla; Amparo Cano; Antonio García d...; Miguel Lafarga; Alberto Muñoz
• Keywords: 0301 basic medicine; Macromolecular Substances; Active Transport, Cell Nucleus; Antineoplastic Agents; Adenocarcinoma; Ligands; 03 medical and health sciences; Calcitriol; Humans; RNA, Messenger; Vitamin D; Research Articles; Cholecalciferol; Cell Membrane; E-cadherin; Cell Differentiation; β-catenin; Cadherins; Colon cancer; 3. Good health; Gene Expression Regulation, Neoplastic; Cytoskeletal Proteins; Phenotype; Vitamin D receptor; Colonic Neoplasms; Receptors, Calcitriol; Cell Adhesion Molecules; Protein Binding; Signal Transduction

The β-catenin signaling pathway is deregulated in nearly all colon cancers. Nonhypercalcemic vitamin D3 (1α,25-dehydroxyvitamin D3) analogues are candidate drugs to treat this neoplasia. We show that these compounds promote the differentiation of human colon carcinoma SW480 cells expressing vitamin D receptors (VDRs) (SW480-ADH) but not that of a malignant subline (SW480-R) or metastasic derivative (SW620) cells lacking VDR. 1α,25(OH)2D3 induced the expression of E-cadherin and other adhesion proteins (occludin, Zonula occludens [ZO]-1, ZO-2, vinculin) and promoted the translocation of β-catenin, plakoglobin, and ZO-1 from the nucleus to the plasma membrane. Ligand-activated VDR competed with T cell transcription factor (TCF)-4 for β-catenin binding. Accordingly, 1α,25(OH)2D3 repressed β-catenin–TCF-4 transcriptional activity. Moreover, VDR activity was enhanced by ectopic β-catenin and reduced by TCF-4. Also, 1α,25(OH)2D3 inhibited expression of β-catenin–TCF-4-responsive genes, c-myc, peroxisome proliferator-activated receptor δ, Tcf-1, and CD44, whereas it induced expression of ZO-1. Our results show that 1α,25(OH)2D3 induces E-cadherin and modulates β-catenin–TCF-4 target genes in a manner opposite to that of β-catenin, promoting the differentiation of colon carcinoma cells.