Insulin-like Growth Factor 1 Induces Hypoxia-inducible Factor 1-mediated Vascular Endothelial Growth Factor Expression, Which is Dependent on MAP Kinase and Phosphatidylinositol 3-Kinase Signaling in Colon Cancer Cells

Johns Hopkins University, Baltimore, Maryland, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2002; 277(41):38205-11. DOI: 10.1074/jbc.M203781200
Source: PubMed


Stimulation of human colon cancer cells with insulin-like growth factor 1 (IGF-1) induces expression of the VEGF gene, encoding vascular endothelial growth factor. In this article we demonstrate that exposure of HCT116 human colon carcinoma cells to IGF-1 induces the expression of HIF-1 alpha, the regulated subunit of hypoxia-inducible factor 1, a known transactivator of the VEGF gene. In contrast to hypoxia, which induces HIF-1 alpha expression by inhibiting its ubiquitination and degradation, IGF-1 did not inhibit these processes, indicating an effect on HIF-1 alpha protein synthesis. IGF-1 stimulation of HIF-1 alpha protein and VEGF mRNA expression was inhibited by treating cells with inhibitors of phosphatidylinositol 3-kinase and MAP kinase signaling pathways. These inhibitors also blocked the IGF-1-induced phosphorylation of the translational regulatory proteins 4E-BP1, p70 S6 kinase, and eIF-4E, thus providing a mechanism for the modulation of HIF-1 alpha protein synthesis. Forced expression of a constitutively active form of the MAP kinase kinase, MEK2, was sufficient to induce HIF-1 alpha protein and VEGF mRNA expression. Involvement of the MAP kinase pathway represents a novel mechanism for the induction of HIF-1 alpha protein expression in human cancer cells.

    • "harboring the activating BFAFV600E or RAS mutations (27), activation of the phosphatidylinositol 3-kinase (PI3K) pathway (Kuphal S et al. Eur J of Cancer 2010, Fukuda et al. J Biol Chem 2002)(24, 28) or the endothelin-dependent signaling pathway (29), and upregulation of the NF-KB mediated pathway (24). High expression of the anti-apoptotic protein Bcl-2 (30) and inhibition of prolyl hydroxylase by the melanoma-specific antigen MAGE-11 (31) have been also reported."
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    • "The increased mRNA of HIF-1α might be a compensatory effect in response to the repression of HIF-1α protein synthesis. On the other hand, the protein synthesis of HIF-1α protein can be regulated by growth factor-stimulation via mTOR mediated activation of p70 S6K and 4E-BPs [11]. In the present study, our results reveal that mitochondrial dysfunction reduces HIF-1α protein synthesis in HepG2 cells. "
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    • "Signaling via receptor tyrosine kinases can induce HIF-1 expression by a mechanism independent of the presence of hypoxia. HER2/neu and IGF-1 receptor activation increases the rate of HIF-1α protein synthesis (Fukuda et al., 2002; Laughner et al., 2001). "
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