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

By H. G. Pálmer, J. González-Sancho, J. Espada, M. Berciano, I. Puig, J. Baulida, M. Quintanilla, A. Cano, A. G. de Herreros, M. Lafarga and 1 more. Journal of Cell Biology, 2001

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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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a3da5d6760af434a8ab5fdc20a96c000c68c6107

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Citations in the corpus

Vitamin D and human health: lessons from vitamin D receptor null mice. (2008, background): “Since then, the antineoplastic activity of 1,25-(OH)2D was shown both in vitro and in vivo in a wide variety of malignancies, such as leukemia (266, 267) and colon (268, 269), breast (270–272), and prostate cancer (273, 274).”
Nonclassic actions of vitamin D. (2009, background): “In particular 1,25(OH)2D stimulates the expression of cell cycle inhibitors p21 and p27 (88) and the expression of the cell adhesion molecule E-cadherin (89) and inhibits the transcriptional activity of -catenin (89 – 91).”
The nonskeletal effects of vitamin D: an Endocrine Society scientific statement. (2012, background): “Studies directed at identifying molecular partners of the unliganded VDR that play a role in the regulation of keratinocyte stem cell function demonstrated that, in contrast to investigations demonstrating that the liganded VDR impairs canonical Wnt signaling (30, 78), the unliganded VDR is essentia”
Noncalcemic actions of vitamin D receptor ligands. (2005, background): “In these cells, 1,25-(OH)2D3 also promoted the translocation of -catenin, plakoglobin, and ZO-1 from the nucleus to the plasma membrane.”
The cadherin-catenin adhesion system in signaling and cancer. (2002, background): “A recent study demonstrated that E-cad mRNA expression and cellcell adhesion are induced in SW480 human colon cancer cells by vitamin D3 (13).”
Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms (2003, background): “Interesting findings by Palmer et al.95 indicate that [1,25(OH) 2 D 3 ] can also have a growth-restraining action at an early stage of colorectal carcinogenesis, at a time when the loss of APC function occurs.”