1alpha,25-Dihydroxyvitamin D3 regulates the expression of Id1 and Id2 genes and the angiogenic phenotype of human colon carcinoma cells.
1alpha,25-Dihydroxyvitamin D3 (1alpha,25(OH)2D3) has antitumor activity in addition to its classical action on calcium metabolism and bone tissue biology. It is thought to regulate the expression of multiple target genes and thus modulate processes critical for tumor growth and metastases. Here we show that 1alpha,25(OH)2D3 differentially regulates the expression of Id1 and Id2 genes, members of a family of transcriptional regulators of cell proliferation and differentiation. 1alpha,25(OH)2D3 induced epithelial differentiation in SW480-ADH human colon carcinoma cell line by promoting expression of the proteins implicated in adherent junction formation, including E-cadherin, and by inhibiting beta-catenin transcriptional activity. 1alpha,25(OH)2D3 activated the human Id1 gene promoter and rapidly induced Id1 RNA and protein. Ectopic overexpression of Id1 was not sufficient to induce E-cadherin, which was critical for the morphological changes induced by 1alpha,25(OH)2D3 in SW480-ADH cells. Conversely, Id2 transcription rate, RNA and protein levels were decreased by 1alpha,25(OH)2D3. Id2 downregulation by 1alpha,25(OH)2D3 mediated the antiproliferative effect of 1alpha,25(OH)2D3 on SW480-ADH cells. In addition, we showed that 1alpha,25(OH)2D3 changed the levels of the inducer of angiogenesis, vascular endothelial growth factor and the potent antiangiogenic factor thrombospondin-1, leading to a balanced change in the angiogenic potential of SW480-ADH human colon carcinoma cells.
Fernandez-Garcia
Nuria Isabel
NI
Instituto de Investigaciones Biomedicas CSIC-UAM, Madrid, Spain.
Palmer
Hector G
HG
Garcia
Marta
M
Gonzalez-Martin
Alicia
A
del Rio
Marcela
M
Barettino
Domingo
D
Volpert
Olga
O
Muñoz
Alberto
A
Jimenez
Benilde
B
D000818:Animals; D015820:Cadherins / Q000187:drug effects / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics*; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C497453:ID1 protein, human; C497450:ID2 protein, human; C497455:Idb1 protein, mouse; C497452:Idb2 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; C118756:dihydroxy-vitamin D3; D014807:Vitamin D