Mechanism of action of vitamin D and the vitamin D receptor in colorectal cancer prevention and treatment

Abstract

Summary Vitamin D and its analogs are potent inhibitors of colorectal cancer growth and metastasis. A number of recent studies have defined the intersections between the β-catenin-TCF pathway (a known contributor to colorectal cancer progression) and the vitamin D receptor (VDR) pathway, shedding light on the underlying mechanisms. Vitamin D also regulates the innate immune response, and as such influences susceptibility to inflammatory bowel disease, a predisposing factor in colorectal cancer. Understanding the role of vitamin D in these different contexts will enable development of next generation vitamin D analogs that will serve as both chemopreventatives and cancer therapeutics, without the accompanying side effects of hypercalcemia usually associated with high vitamin D intake. This review summarizes the mechanisms of action of vitamin D and the VDR in the context of the gastrointestinal tract and colorectal carcinogenesis.

Vitamin D receptor gene <em>Taq</em>I and <em>Apa</em>l polymorphisms and steroid responsiveness in childhood idiopathic nephrotic syndrome

“…The 5′ noncoding end of the gene includes regions of exons 1A, 1B, and 1C. 1 The translated gene product (protein) is encoded by exons 2-9. Exons 7-9 play a critical role in binding to vitamin D. Allelic variations in VDR are involved in their function, suggesting in turn that allelic variations in VDR cause functional differences in the potency of 1,25-dihydroxy D3 as an immunosuppressive hormone.…”

“…1 In the cells, vitamin D exerts its effects through the vitamin D receptor (VDR), a nuclear transcription factor to which vitamin D binds via the carboxyl-terminal ligandbinding domain. The VDR molecule belongs to a large class of nuclear receptors that include thyroid, steroid, and retinoic acid receptors.…”

Vitamin D in cancer chemoprevention

“…A consistent number of investigations provide evidence that 1,25(OH) 2 D 3 and its semisynthetic analogues may play a key role in the prevention and treatment of colorectal cancer (Byers et al, 2012;Leyssens et al, 2013;Pereira et al, 2012 (Matusiak et al, 2005). The activation of VDR elicits antitumor effects by triggering apoptosis and by inhibiting cell proliferation, invasion, and angiogenesis (González-Sancho et al, 2006;Pendás-Franco et al, 2008a;Samuel & Sitirin, 2008).…”

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

“…VDR forms a heterodimer with Retinoid X receptor (RXR) and its ligand (9 cis-retinoic acid) (Carlberg and Seuter, 2009). When 1, 25(OH) 2 D is absent, VDR-RXR heterodimer binds to a specific sequence within its target vitamin D-responsive gene named vitamin D response elements (VDREs) (Byers et al, 2012). Also it binds to transcriptional co-repressors and silencing mediators which maintain a repressed transcriptional state (Pereira et al, 2012).…”