Cellular and molecular effects of vitamin D on carcinogenesis

Abstract

Epidemiologic data suggest that the incidence and severity of many types of cancer inversely correlates with indices of vitamin D status. The vitamin D receptor (VDR) is highly expressed in epithelial cells at risk for carcinogenesis including those resident in skin, breast, prostate and colon, providing a direct molecular link by which vitamin D status impacts on carcinogenesis. Consistent with this concept, activation of VDR by its ligand 1,25-dihydroxyvitamin D (1,25D) triggers comprehensive genomic changes in epithelial cells that contribute to maintenance of the differentiated phenotype, resistance to cellular stresses and protection of the genome. Many epithelial cells also express the vitamin D metabolizing enzyme CYP27B1 which enables autocrine generation of 1,25D from the circulating vitamin D metabolite 25-hydroxyvitamin D (25D), critically linking overall vitamin D status with cellular anti-tumor actions. Furthermore, pre-clinical studies in animal models has demonstrated that dietary supplementation with vitamin D or chronic treatment with VDR agonists decreases tumor development in skin, colon, prostate and breast. Conversely, deletion of the VDR gene in mice alters the balance between proliferation and apoptosis, increases oxidative DNA damage, and enhances susceptibility to carcinogenesis in these tissues. Because VDR expression is retained in many human tumors, vitamin D status may be an important modulator of cancer progression in persons living with cancer. Collectively, these observations have reinforced the need to further define the molecular actions of the VDR and the human requirement for vitamin D in relation to cancer development and progression.

Inverse association between circulating vitamin D and mortality – Dependent on sex and cause of death?

“…Children with 2 deficiency may suffer from rickets and adults from osteomalacia. Since several years, however, 3 vitamin D is of interest with respect to the risk of other chronic diseases [1] because it has 4 immunomodulation properties [2] as well as effects on cell differentiation and proliferation [3], on 5 angiogenesis, but also on blood pressure and glucose tolerance [4]. Therefore, it was suggested that 6 low levels of vitamin D may also increase the risk of death.…”

Serum 25-Hydroxyvitamin D and Cancer Risk in Older Adults: Results from a Large German Prospective Cohort Study

“…The biologically active form of vitamin D, calcitriol, or 1,25-dihydroxyvitamin D [1,25(OH) 2 D], which is generated by the kidneys and other epithelial tissues, reduces cell proliferation, and induces cell differentiation and apoptosis (7)(8)(9). In addition, the vitamin D receptor (VDR) is activated by 1,25 (OH) 2 D and mediates genomic changes in epithelial cells that contribute to a preservation of the differentiated phenotype, resistance to cellular stress, and protection of the genome (10).…”

Association between Circulating Vitamin D, the Taq1 Vitamin D Receptor Gene Polymorphism and Colorectal Cancer Risk among Jordanians

“…The second hydroxylation occurs in the kidney where 25(OH)D is converted to the active form 1, 25 dihydroxyvitamin D (1,25(OH) 2 D) (Holick et al, 2011). The main role of 1, 25(OH) 2 D is calcium-phosphate homeostasis (Verstuyf et al, 2010), regulation of cell cycle (Pereira et al, 2012), and nowadays it has anticancer effect especially among colon cancer (Holick etal., 2011;Welsh, 2012 (Haussler et al, 2011). VDR is a protein consists of 427 amino acids, with a molecular weight of about forty eight KDa (Bouillon et al, 2008).…”