Molecular actions of vitamin D contributing to cancer prevention

Abstract

The population-based relationship between low vitamin D status and increased cancer risk is now generally accepted. While these relationships are between serum 25 hydroxyvitamin D and cancer, cell-based studies show that the metabolite 1,25 dihydroxyvitamin D is biologically active and influences cell biology relevant to cancer through vitamin D receptor-mediated gene transcription. This review examines this paradox and also discusses the cell and gene targets influenced by 1,25 dihydroxyvitamin D that may account for the anti-cancer actions of vitamin D. A review of the literature shows that while vitamin D-induced growth arrest and apoptosis of tumor cells or their non-neoplastic progenitors are plausible mechanisms, other gene targets related to DNA repair and immunomodulation, and other cell targets such as the stromal cells and cells of the immune system, may be regulated by 1,25 dihydroxyvitamin D and contribute to vitamin D mediated cancer prevention.

Figure 1

A summary of the molecular targets affected by 1,25(OH)₂ D. Cell-based studies and microarray analysis suggest that 1,25(OH)₂ D action can influence many cellular systems directly through transcriptional events mediated through the vitamin D receptor (VDR)-retinoid X receptor (RXR) heterodimer or indirectly by using the VDR to interfere with beta catenin signaling.

Figure 2

The relationship between vitamin D metabolism, vitamin D action, and cancer. (A) Transcriptional activation of genes through the vitamin D receptor (VDR) is dependent upon both the production of the active metabolite, 1,25(OH)₂ D, through the enzyme CYP27b1, and its degradation by the enzyme CYP24. (B) A schematic demonstrating how the process of cancer may influence vitamin D action.