1α,25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells

In vitro and in vivo studies have shown that 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] inhibits angiogenesis in cancer. Ne now examined whether the antiangiogenic effects of 1,25(OH)(2)D-3 are mediated by the hypoxia-inducible factor (HIF)-1 pathway. Our results showed that 1,25(OH)21)3 reduces the protein expression of both the regulated HIF-1 alpha subunit and the vascular endothelial growth fa,tor (VEGF) in various human cancer cells. 1,25(OH)21)3 also inhibited HIF-1 transcriptional activity (measured by reporter gene assay) as well as HIF-1 target genes, including VEGF, ET-1, and Glut-1. We also showed that 1,25(OH)2D3 inhibits cell proliferation under hypoxia. Using HIF. 1 a knockout colon cancer cells, we show that the inhibition of the hypoxia-induced VEGF by 1,25(OH)21)3 is mediated through a HIF-dependent pathway. Because HIF-1 is a major positive contributor in human tumorigenesis and angiogenesis, we believe that its inhibition by 1,25(OH)2D3 strengthens the rationale to use vitamin D and its low-calcemic analogues in cancer chemoprevention and therapy.