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9--D-Arabinofuranosyl-2-fluoroadenine Inhibits Expression of Vascular Endothelial Growth Factor through Hypoxia-Inducible Factor-1 in Human Ovarian Cancer Cells

Mary Babb Randolph Cancer Center, Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia (J.F., Z.C., E.R., B.-H.J.); and Natural Science Division, Alderson-Broaddus College, Philippi, West Virginia (Y.C.C.)

Ovarian cancer is the leading cause of death from gynecological malignancy and has the worst prognosis of all gynecological cancers. Vascular endothelial growth factor (VEGF) plays an important role in ovarian cancer development. 9--D-Arabinofuranosyl-2-fluoroadenine (Fara-A), a nucleotide analog, is frequently used in treating certain types of cancer. However, the effectiveness of Fara-A on ovarian cancer cells is unknown. In this study, we found that Fara-A inhibited VEGF expression in human ovarian cancer cells. Fara-A inhibited VEGF transcriptional activation through hypoxia-inducible factor 1 (HIF-1). HIF-1 is composed of HIF-1 and -1 subunits. Fara-A inhibited expression of HIF-1 but not HIF-1. Overexpression of HIF-1 reversed Fara-A-inhibited VEGF transcriptional activation. Our results demonstrated that Fara-A inhibited VEGF transcriptional activation through HIF-1 expression. Fara-A partly inhibited HIF-1 mRNA levels. Fara-A blocked the activation of AKT but not of ERK1/2. Overexpression of AKT reversed the Fara-A-inhibited VEGF transcriptional activation, suggesting that Fara-A inhibits VEGF expression via phosphatidylinositol 3-kinase/AKT signaling. These results demonstrate a new function of Fara-A in inhibiting VEGF and HIF-1 expression and identify a potential molecular mechanism of the regulation.

Address correspondence to: Bing-Hua Jiang, Mary Babb Randolph Cancer Center, Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506-9300. E-mail: bhjiang{at}hsc.wvu.edu

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