TY - JOUR T1 - Long-term Channel Block is Required to Inhibit Cellular Transformation by Human Ether-a-go-go-related Gene (Herg1) Potassium Channels JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.113.091439 SP - mol.113.091439 AU - David M Pier AU - George SG Shehatou AU - Susan Giblett AU - Christine E Pullar AU - Derek J Tresize AU - Catrin A Pritchard AU - John Challiss AU - John S Mitcheson Y1 - 2014/01/01 UR - http://molpharm.aspetjournals.org/content/early/2014/05/14/mol.113.091439.abstract N2 - hERG1 and the closely related hEAG1 channel are aberrantly expressed in a large proportion of human cancers. In the present study we demonstrate that transfection of hERG1 into mouse fibroblasts is sufficient to induce many features characteristic of malignant transformation. Importantly, this transformation could be reversed by chronic incubation (for 2-3 weeks) with the hERG channel blocker dofetilide (100nM), while more acute applications (for 1-2 days) were ineffective. hERG1 expression resulted in a profound loss of cell contact inhibition, multiple layers of over-growing cells and high saturation densities. Cells also changed from fibroblast-like to a more spindle-shaped morphology, which was associated with a smaller cell size, a dramatic increase in cell polarization, a reduction in the number of actin stress fibres and less punctate labeling of focal adhesions. Analysis of single cell migration and scratch wound closure clearly demonstrated that hERG1-expressing cells migrated more rapidly than vector-transfected control cells. In contrast to previous studies on hEAG1, there were no increases in rates of proliferation, or loss of growth factor-dependency, however, hERG1-expressing cells were capable of substrate-independent growth. Allogeneic transplantation of hERG1-expressing cells into nude mice resulted in an increased incidence of tumors. In contrast to hEAG1, the mechanism of cellular transformation is dependent on ion conduction. Trafficking deficient and conduction deficient hERG1 mutants also prevented cellular transformation. These results provide evidence that hERG1 expression is sufficient to induce cellular transformation by a mechanism distinct from hEAG1. Importantly, selective hERG1 channel blockers have therapeutic potential in the treatment of hERG1-expressing cancers. ER -