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Research Articles: Therapeutics, Targets, and Development

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

¹ Department of Pediatrics, Dana Children's Hospital; ² Prostate Cancer Research Laboratory, Department of Urology; and ³ Bone Disease Unit, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv, Israel; and ⁴ Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical Center, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan

Requests for reprints: Nicola J. Mabjeesh, Prostate Cancer Research Laboratory, Department of Urology, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel. Phone: 972-3-6974544; Fax: 972-3-6973183. E-mail: nicolam{at}tasmc.health.gov.il

Abstract

In vitro and in vivo studies have shown that 1,25-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-1 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-1 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. [Mol Cancer Ther 2007;6(4):1433–9]

Grant support: M.K. Humanitarian Association, PCF Israel, Bat Sheva De Rothschild Foundation Grant of the Israel Ministry of Health and the Israel Academy of Science in memory of the late Professors A. Eldor and Y. Matzner, and the Israel Cancer Association through the Ben-Lehmsdorf Memorial Fund in memory of the late John Furman.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/ 3/06; revised 2/12/07; accepted 2/21/07.

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