Vitamin D is an example of a nutrient that exhibits many of the mechanisms described above in inhibiting cancer development, particularly in inhibition of proliferation, induction of differentiation, activation of apoptosis, and blocking initiation. Vitamin D and its analogs have been investigated for some time for their anticancer properties in a number of cancers, including colorectal, prostate, breast, and leukemia.9 The classical role of the most bioactive form of vitamin D, 1a,25-dihydroxyvitamin D3 (1a,25(OH)2D3), is to regulate calcium absorption in the intestine, maintain mineral homeostasis in the kidney, and regulate bone remodeling. This function can lead to toxic hypercalcemia when exogenous 1a,25(OH)2D3 is administered in therapeutic doses; therefore, a number of pharmaceutical analogs have been developed that retain their anticancer properties with minimal effects on circulating calcium.71 Many tissues other than those involved with mineral metabolism have specific vitamin D nuclear receptors, suggesting alternative roles for vitamin D. Normal and cancer cells that express vitamin D receptors respond to 1a,25(OH)2D3 by decreasing proliferation and enhancing maturation or differentiation.72 In addition, many cell types, including notably colon cancer cells,73 74 can make 1a,25(OH)2D3, suggesting autocrine/paracrine actions in manipulating cell growth.
1a,25(OH)2D3 has direct antiproliferative properties against many cancer cells in vitro, including colon,75-78 breast,7980 prostate,8182 and hematopoietic cells.83 Also, 1a,25(OH)2D3 and its metabolic precursor, 25(OH)2D3, reduce crypt cell production in colonic tissue removed from individuals with familial adenom-atous polyposis (an inherited cancer syndrome caused by a mutation in the Apc gene).84 Whether the antiproliferative effects of vitamin D are totally independent of calcium level is not clear. For example, the effect of vitamin D in colon cancer cells in vitro varies by extracellular calcium concentration85 and is reduced by addition of calcium channel blockers.75
The anticarcinogenic activity of 1a,25(OH)2D3 appears to be correlated with cellular vitamin D receptor (VDR) levels. VDRs belong to the superfamily of steroid-hormone zinc-finger receptors and share the common characteristic with other members of this family in that they are ligand-activated regulators of gene transcription. VDRs selectively bind 1a,25(OH)2D3 and RXR to form a het-erodimeric complex that interacts with specific DNA sequences known as vitamin D-responsive elements (VDRE) to regulate gene expression. For example, the binding of 1a,25(OH)2D3 to the VDR in intestinal cells activates the transcription of the calcium-binding protein that enhances the absorption of calcium.
The VDR is expressed in colon tumor cells,7586 and the density of the vitamin D receptor is increased in hyperplastic polyps and in early stages of tumorigenesis, but declines in late-stage neoplasia.748788 With carcinogen treatment, rats show a decreased number of 1a,25(OH)2D3 binding sites in the colon.89 The level of vitamin D receptor in wild-type, heterozygote, and vitamin D receptor null mice is inversely correlated with proliferating nuclear cell antigen and cyclin D1, markers of cellular proliferation, and positively correlated with 8-hydroxy-2'-deoxyguanosine levels, a marker of oxidative stress in the colon descendens.90 These results implicate genomic 1a,25(OH)2D3 action in prevention of hyperpro-liferation and oxidative DNA damage.
The activated receptor recognizes specific vitamin D response elements in a number of vitamin D-regulated genes, including p21WAF1 and the calcium-sensing receptor. However, vitamin D regulates a number of different proto-oncogenes and tumor suppressor genes related to proliferation and differentiation, including p27KIP1, c-myc, laminin, tenascin, fibronectin, cyclin C, c-fos, c-jun, phospholipase Cy ornithine decarboxylase, and members of the TGF-P family.91 As not all of these genes have vitamin D response element consensus sequences identified in their promoter regions, their regulation is thought to be indirect through regulation of upstream events or even activation of a putative membrane-bound receptor.
The anticancer effects restricting cellular growth are thought to involve various mechanisms, including effects on growth factor and cytokine synthesis and signaling, cell cycle progression, apoptosis, and differentiation. An example of the regulation by 1a,25(OH)2D3 of a growth-factor signaling pathway is that of TGF-P, which inhibits epithelial cell proliferation. SMAD3, a downstream protein in the TGF-P signaling pathway, is a coactivator of the vitamin D receptor and positively regulates the vitamin D signaling pathway.92-94 Cross talk between vitamin D and TGF-P 1 has been demonstrated in the growth inhibition of human colon cancer-derived cells.95 The antimitotic actions of vitamin D and its analogs seem to be mediated by the induction of G1 cell cycle arrest, resulting from the upregulation of expression of p21WAF1 and p27HP1.'96-98
In addition to inhibiting tumor growth and progression, 1a,25(OH)2D3 has anticancer action by inducing apoptosis in various transformed cells, including colon cancer cells.96,99 The mechanisms of the proapoptotic action in colon cells is not entirely clear, but in human colon adenoma and carcinoma cell lines the apoptotic action of vitamin D was associated with upregulation of the expression of the proapoptotic protein Bak.100 The differentiation-promoting effect of 1a,25(OH)2D3 was demonstrated in a human colon carcinoma cell line, SW480, which expresses vitamin D receptors, but not in other similar lines that do not express the receptor. 1a,25(OH)2D3 induced the expression of proteins associated with the mature phenotype, such as E-cadherin and cell adhesion proteins, and repressed P-catenin signaling, which has an antitumor effect in vivo.101
The VDR also has been postulated to have a role in suppressing initiation of colon carcinogenesis. The VDR has been shown to have high affinity for the secondary bile acid lithocholic acid LCA and its metabolites, which are carcinogenic. By binding to the vitamin D receptor, both LCA and vitamin D may activate a feed-forward catabolic pathway that increases the expression of CYP3A, a cytochrome P450 enzyme that detoxifies LCA in the liver and intestines to clear LCA from the body.102 This may provide one mechanism to explain how the protective pathway of vitamin D receptor activation may become overwhelmed by high-fat diets (which increase LCA levels) or compromised when vitamin D is deficient with inadequate sun exposure or intake.
Studies using carcinogen-induced intestinal cancer models show the effect in vivo of vitamin D alone or in combination with calcium on the development of intestinal cancer. Rats on a high-fat (20% corn oil) diet had increased tumor incidence after 1,2-dimethylhydrazine (DMH) treatment, and this increase was ameliorated by either supplemental calcium or vitamin D.103 104 Conversely, vitamin D deficiency abolished the protective effects of calcium on colon cancer in DMH-treated rats.105 106 1a,25(OH)2D3 before treatment with DMH obliterated the peak in ornithine decarboxylase activity (a sign of increased mucosal cell proliferation) seen with DMH administration, and reduced by 50% the number of colon adenocarcinomas.89 However, in this and a similar study,107 1a,25(OH)2D3 did not prevent tumor formation when administered after DMH. One mechanism of the chemopreventive action of 1a,25(OH)2D3 treatment elucidated in AOM-treated rats was an inhibition in angiogenesis, defined as a decrease in immunohistochemical staining for vascular endothelial growth factor and microvessel counts.108 In our own studies using mutant mice, we found that administration of 1a,25(OH)2D3 and an analog of vitamin D to Apcmin mice, which have a germ line mutation in the Apc tumor suppressor gene, resulted in a significant decrease in total tumor area over the entire gastrointestinal tract in both the analog- and the 1a,25(OH)2D3-treated groups.109
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