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

Moshe Ben-Shoshan, Sharon Amir, Duyen T. Dang, Long H. Dang, Yosef Weisman, Nicola J. Mabjeesh

Research output: Contribution to journalArticlepeer-review

Abstract

In vitro and in vivo studies have shown that 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibits angiogenesis in cancer. We now examined whether the antiangiogenic effects of 1,25(OH)2D3 are mediated by the hypoxia-inducible factor (HIF)-1 pathway. Our results showed that 1,25(OH)2D3 reduces the protein expression of both the regulated HIF-1α subunit and the vascular endothelial growth factor (VEGF) in various human cancer cells. 1,25(OH)2D3 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-1α knockout colon cancer cells, we show that the inhibition of the hypoxia-induced VEGF by 1,25(OH)2D3 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.

Original languageEnglish
Pages (from-to)1433-1439
Number of pages7
JournalMolecular Cancer Therapeutics
Volume6
Issue number4
DOIs
StatePublished - Apr 2007
Externally publishedYes

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