title: hERG1 channels modulate integrin signaling to trigger angiogenesis and tumor progression in colorectal cancer.
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.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence and Istituto Toscano Tumori (ITT), Florence, Italy.
authors.forename: Olivia
authors.initials: O
authors.lastname: Crociani
authors.forename: Francesca
authors.initials: F
authors.lastname: Zanieri
authors.forename: Serena
authors.initials: S
authors.lastname: Pillozzi
authors.forename: Elena
authors.initials: E
authors.lastname: Lastraioli
authors.forename: Matteo
authors.initials: M
authors.lastname: Stefanini
authors.forename: Antonella
authors.initials: A
authors.lastname: Fiore
authors.forename: Angelo
authors.initials: A
authors.lastname: Fortunato
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Amico
authors.forename: Marika
authors.initials: M
authors.lastname: Masselli
authors.forename: Emanuele
authors.initials: E
authors.lastname: De Lorenzo
authors.forename: Luca
authors.initials: L
authors.lastname: Gasparoli
authors.forename: Martina
authors.initials: M
authors.lastname: Chiu
authors.forename: Ovidio
authors.initials: O
authors.lastname: Bussolati
authors.forename: Andrea
authors.initials: A
authors.lastname: Becchetti
authors.forename: Annarosa
authors.initials: A
authors.lastname: Arcangeli
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051638:Ether-A-Go-Go Potassium Channels; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019012:Integrin beta1; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C496884:KCNH1 protein, human