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A more recent version of this article appeared on November 1, 2004
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Submitted on May 7, 2004
Revised on August 18, 2004
Accepted on August 19, 2004
Departments of *Radiation Oncology and ||Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19004; Department of Radiation Oncology and Cancer Research Institute, University of California, San Francisco, CA 94143; Institute of Signaling, Developmental Biology, and Cancer Research, Nice, France
Monitoring Editor: Mark Ginsberg
Increased expression of vascular endothelial growth factor (VEGF) contributes to the growth of many tumors by increasing angiogenesis. While hypoxia is a potent inducer of VEGF, we previously showed that EGFR amplification and loss of PTEN, both of which can increase phosphatidylinositol-3-kinase (PI3K) activity, increase VEGF expression. Using both adenoviral vectors and a cell line permanently expressing constitutively active myristoylated Akt (myrAkt), we show that activation of Akt, which is downstream of PI3K, increases VEGF expression in vitro and increases angiogenesis in a Matrigel plug assay. Transient transfection experiments using reporter constructs containing the VEGF promoter showed that upregulation of VEGF by Akt is mediated through Sp1 binding sites located in the proximal promoter. Small interfering RNA directed against Sp1 prevented the induction of VEGF mRNA in response to myrAkt but not to hypoxia. Expression of myrAkt is associated with increased phosphorylation of Sp1 and its increased binding to a probe corresponding to the -88/-66 promoter region. In conclusion, our results indicate that Sp1 is required for transactivation of the VEGF by Akt. Others have proposed that the PI3K/Akt pathway can increase VEGF expression via the hypoxia-inducible factor 1 (HIF-1); however, our results suggest an alternative mechanism can also operate.
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