Long-term channel block is required to inhibit cellular transformation by human ether-à-go-go-related gene (hERG1) potassium channels

Both human ether-à-go-go-related gene (hERG1) and the closely related human ether-à-go-go (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 char...

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Bibliographic Details
Published in:	Molecular pharmacology Vol. 86; no. 2; p. 211
Main Authors:	Pier, David M, Shehatou, George S G, Giblett, Susan, Pullar, Christine E, Trezise, Derek J, Pritchard, Catrin A, Challiss, R A John, Mitcheson, John S
Format:	Journal Article
Language:	English
Published:	United States 01-08-2014
Subjects:	Actins - metabolism Animals Cell Line Cell Movement - drug effects Cell Proliferation - drug effects Cell Transformation, Neoplastic - drug effects Cell Transformation, Neoplastic - metabolism Ether-A-Go-Go Potassium Channels - antagonists & inhibitors Ether-A-Go-Go Potassium Channels - metabolism Fibroblasts - drug effects Focal Adhesions - metabolism Humans Mice Mice, Nude NIH 3T3 Cells Potassium Channel Blockers - pharmacology Stress Fibers - metabolism Transfection
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Summary:	Both human ether-à-go-go-related gene (hERG1) and the closely related human ether-à-go-go (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. An important finding of this work is that this transformation could be reversed by chronic incubation (for 2-3 weeks) with the hERG channel blocker dofetilide (100 nM), whereas more acute applications (for 1-2 days) were ineffective. The hERG1 expression resulted in a profound loss of cell contact inhibition, multiple layers of overgrowing 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 fibers, 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. The most important conclusion of this study is that selective hERG1 channel blockers have therapeutic potential in the treatment of hERG1-expressing cancers.
ISSN:	1521-0111
DOI:	10.1124/mol.113.091439