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

McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
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.

119 Reads
    • "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."
    [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, our knowledge regarding the metabolism of melanoma has greatly advanced and consequently new therapeutic strategies are being developed. This review is focused on metabolic path ways contributing to melanoma proliferation, the influence of BRAF inhibitors on those metabolic pathwaysand finally a presentation of potential therapeutic strategies aimed at blocking metabolic signaling pathways and thereforemelanoma development.
    Current cancer drug targets 04/2014; 14(4). DOI:10.2174/1568009614666140407113124 · 3.52 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common malignancies and is ranked third in mortality among cancer-related diseases. Mitochondria are intracellular organelles that are responsible for energy metabolism and cellular homeostasis, and mitochondrial dysfunction has been regarded as a hallmark of cancer. Over the past decades, several types of mitochondrial DNA (mtDNA) alterations have been identified in human cancers, including HCC. However, the role of these mtDNA alterations in cancer progression is unclear. In this review, we summarize the recent findings on the somatic mtDNA alterations identified in HCC and their relationships with the clinicopathological features of HCC. Recent advances in understanding the potential roles of somatic mtDNA alterations in the progression of HCC are also discussed. We suggest that somatic mtDNA mutations and a decrease in the mtDNA copy number are common events in HCC and that a mitochondrial dysfunction-activated signaling cascade may play an important role in the progression of HCC. Elucidation of the retrograde signaling pathways in HCC and the quest for strategies to block some of these pathways will be instrumental for the development of novel treatments for this and other malignancies.
    World Journal of Gastroenterology 12/2013; 19(47):8880-8886. DOI:10.3748/wjg.v19.i47.8880 · 2.37 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostaglandin E1 (PGE1), known pharmaceutically as alprostadil, has vasodilatory properties and is used widely in various clinical settings. In addition to acute vasodilatory properties, PGE1 may exert beneficial effects by altering protein expression of vascular cells. PGE1 is reported to be a potent stimulator of angiogenesis via upregulation of VEGF expression, which is under the control of the transcription factor hypoxia-inducible factor 1 (HIF-1). However, the molecular mechanisms behind the phenomenon are largely unknown. In the present study, we investigated the mechanism by which PGE1 induces HIF-1 activation and VEGF gene expression in human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs), both vascular-derived cells. HUVECs and HASMCs were treated with PGE1 at clinically relevant concentrations under 20% O2 conditions and HIF-1 protein expression was investigated. Expression of HIF- 1α protein and the HIF-1-downstream genes were low under 20% O2 conditions and increased in response to PGE1 treatment in both HUVECs and HASMCs in a dose- and time-dependent manner under 20% O2 conditions as comparable to exposure to 1% O2 conditions. Studies using EP-receptor-specific agonists and antagonists revealed that EP1 and EP3 are critical to PGE1-induced HIF-1 activation. In vitro vascular permeability assays using HUVECs indicated that PGE1 increased vascular permeability in HUVECs. Thus, we demonstrate that PGE1 induces HIF- 1α protein expression and HIF-1 activation under non-hypoxic conditions and also provide evidence that the activity of multiple signal transduction pathways downstream of EP1 and EP3 receptors is required for HIF-1 activation.
    PeerJ 11/2013; 1(1):e220. DOI:10.7717/peerj.220 · 2.11 Impact Factor
Show more