The Anti-cancer Actions of Vitamin D

Vitamin D-3 is biologically inert. To become active, it requires two successive hydroxylation steps catalyzed by two cytochrome P450 enzymes, first to synthesize the pro-hormone 25-hydroxyvitamin D-3 [25(OH)D-3] and then the active hormone 1 alpha,25-dihydroxyvitamin D-3 [1 alpha,25(OH)(2)D-3]. 1 alpha,25(OH)(2)D-3 has high affinity for the vitamin D receptor (VDR), a transcription factor and a member of the steroid receptor superfamily. Through VDR, 1 alpha,25(OH)(2)D-3 regulates more than 200 genes in mammals, including those involved in the calcium and phosphorus homeostasis, immune function, reproduction, cardiovascular, central nerve system, inflammation, angiogenesis, and cellular proliferation, differentiation and apoptosis. Due to its versatile roles in maintaining and regulating normal cellular phenotypes and functions, 1 alpha,25(OH)(2)D-3 has been implicated as an anti-cancer agent. In fact, ecological and epidemiologic data have linked vitamin D deficiency with the incidence and mortality of many types of cancer. More importantly, in vitro and in vivo animal model studies have clearly demonstrated the anti-tumor effects of vitamin D. In this review, we describe the anticancer actions of vitamin D, with special emphasis on different pathways underlying the VDR-mediated genomic as well as less-defined non-genomic actions of vitamin D.