Abstract
Recent reports have suggested that phosphatidylinositol 3-kinase/Akt signaling can induce angiogenesis and tumor growth by activating the hypoxia-inducible factor-1 (HIF-1). However, the absence of specific biochemical inhibitors of HIF-1 signaling has prevented a direct test of the requirement for HIF-1 activity in Akt-dependent tumorigenesis. To genetically test the relationship between HIF-1 and Akt, activated Akt was expressed in a hepatoma cell line lacking HIF-1. Akt expression was associated with a dramatic increase in tumor size, despite the absence of HIF-1. Tumor size was not further increased in cells with reconstituted HIF-1 activity, indicating that the effects of Akt on tumorigenesis were not limited by the absence of HIF-1. Increased tumor size in Akt-expressing, HIF-deficient cells was associated with vascular endothelial growth factor secretion and tumor vascularization. In addition to vascular endothelial growth factor production, Akt also conferred a cell-autonomous competitive advantage to tumor cells in an in vivo competition experiment. Thus, Akt has potent, HIF-1-independent oncogenic and angiogenic activities.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Division
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / physiology*
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Liver Neoplasms, Experimental / blood supply*
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Liver Neoplasms, Experimental / genetics
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Liver Neoplasms, Experimental / metabolism
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Liver Neoplasms, Experimental / pathology*
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Mice
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Mice, Nude
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Neovascularization, Pathologic / enzymology
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / pathology*
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Nuclear Proteins / deficiency
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Nuclear Proteins / physiology*
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-akt
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Transcription Factors*
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Vascular Endothelial Growth Factor A / biosynthesis
Substances
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DNA-Binding Proteins
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Nuclear Proteins
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Proto-Oncogene Proteins
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt