Abstract
Substantive evidence implicates vitamin D receptor (VDR) or its natural ligand 1α,25-(OH)2 D3 in modulation of tumor growth. However, both human and animal studies indicate tissue-specificity of effect. Epidemiological studies show both inverse and direct relationships between serum 25(OH)D levels and common solid cancers. VDR ablation affects carcinogen-induced tumorigenesis in a tissue-specific manner in model systems. Better understanding of the tissue-specificity of vitamin D-dependent molecular networks may provide insight into selective growth control by the seco-steroid, 1α,25-(OH)2 D3. This commentary considers complex factors that may influence the cell- or tissue-specificity of 1α,25-(OH)2 D3/VDR growth effects, including local synthesis, metabolism and transport of vitamin D and its metabolites, vitamin D receptor (VDR) expression and ligand-interactions, 1α,25-(OH)2 D3 genomic and non-genomic actions, Ca2+ flux, kinase activation, VDR interactions with activating and inhibitory vitamin D responsive elements (VDREs) within target gene promoters, VDR coregulator recruitment and differential effects on key downstream growth regulatory genes. We highlight some differences of VDR growth control relevant to colonic, esophageal, prostate, pancreatic and other cancers and assess the potential for development of selective prevention or treatment strategies.
Highlights
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1.9 Tissue - and cell- specificity of vitamin D biological effects - Most tissues an express the receptor for 1α,25-(OH)2 D3 (VDR) and renal tubules, skin, bone, brain, breast, colon and prostate contain the enzyme CYP27B1, required for converting the major circulating metabolite of vitamin D, [25 (OH) D] to 1α,25-(OH)2
E-cadherin is induced by 1α,25-(OH)2 D3 nongenomic rapid actions [67] and suppresses cell growth, partly by inhibition of β-catenin transcriptional activity [72, Ac ce pt e
Summary
HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. E-cadherin and osteopontin (OPN) are functionally antagonistic VDR target genes that orchestrate the growth response to 1α,25-(OH)2 D3 in diverse tumor types. By cross-talk with VDR/VDRE regulation of gene transcription, ip t these membrane-mediated kinase cascades may influence cell-specific biological responses to 1α,25-(OH)2 D3, involved diverse physiological and pathobiological us cr processes [7].
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