1alpha,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 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] inhibits angiogenesis in cancer. We 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)(2)D(3) reduces the protein expression of both the regulated HIF-1alpha subunit and the vascular endothelial growth factor (VEGF) in various human cancer cells. 1,25(OH)(2)D(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)(2)D(3) inhibits cell proliferation under hypoxia. Using HIF-1alpha knockout colon cancer cells, we show that the inhibition of the hypoxia-induced VEGF by 1,25(OH)(2)D(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)(2)D(3) strengthens the rationale to use vitamin D and its low-calcemic analogues in cancer chemoprevention and therapy.
Ben-Shoshan
Moshe
M
Department of Pediatrics, Dana Children's Hospital, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
Amir
Sharon
S
Dang
Duyen T
DT
Dang
Long H
LH
Weisman
Yosef
Y
Mabjeesh
Nicola J
NJ
D002117:Calcitriol / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D014176:Protein Biosynthesis / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D002117:Calcitriol