Abstract
Angiogenesis is a potential target for cancer therapy. We identified a novel signaling pathway that sustains angiogenesis and progression in colorectal cancer (CRC). This pathway is triggered by β1 integrin-mediated adhesion and leads to VEGF-A secretion. The effect is modulated by the human ether-à-go-go related gene 1 (hERG1) K(+) channel. hERG1 recruits and activates PI3K and Akt. This in turn increases the Hypoxia Inducible Factor (HIF)-dependent transcription of VEGF-A and other tumour progression genes. This signaling pathway has novel features in that the integrin- and hERG1-dependent activation of HIF (i) is triggered in normoxia, especially after CRC cells have experienced a hypoxic stage, (ii) involves NF-kB and (iii) is counteracted by an active p53. Blocking hERG1 switches this pathway off also in vivo, by inhibiting cell growth, angiogenesis and metastatic spread. This suggests that non-cardiotoxic anti-hERG1 drugs might be a fruitful therapeutic strategy to prevent the failure of anti-VEGF therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Hypoxia
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Cell Line, Tumor
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology*
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Disease Models, Animal
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Ether-A-Go-Go Potassium Channels / genetics
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Ether-A-Go-Go Potassium Channels / metabolism*
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HCT116 Cells
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HT29 Cells
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Integrin beta1 / metabolism*
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Male
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Mice
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Mice, Nude
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Neovascularization, Pathologic / pathology*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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RNA, Small Interfering / metabolism
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Signal Transduction / drug effects
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Transplantation, Heterologous
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Tumor Suppressor Protein p53 / metabolism
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Ether-A-Go-Go Potassium Channels
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Integrin beta1
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KCNH1 protein, human
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NF-kappa B
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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RNA, Small Interfering
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Tumor Suppressor Protein p53
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Vascular Endothelial Growth Factor A
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endothelial PAS domain-containing protein 1
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Proto-Oncogene Proteins c-akt