Long-Term Channel Block Is Required to Inhibit Cellular Transformation by Human Ether-à-Go-Go–Related Gene (hERG1) Potassium Channels

Abstract

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 substrateindependent 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.

SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness

“…Interestingly, altered motility was paralleled by a reduced capacity for cells to reorganize their actin cytoskeleton, to promote the formation of actin spike, and to change their shape following contact with ECM (46). This result is in line with previous observations showing that hERG expression contributes to morphology, actin cytoskeleton dynamics, and finally cell migration behavior (11). Together, these data reveal that Sig1R participates to cancer migration potency in response to ECM.…”

“…9,10]. hERG expression is sufficient to induce transformation of fibroblasts (11), and in cancer cells, it forms membrane platforms with receptors of the tumor cell microenvironment, such as integrins [adhesion receptors of the extracellular matrix (ECM)], that deeply influences signaling pathways controlling in turn cancer cell spreading (12). Targeting proteins regulating ion channel activity in cancer cells appears as a promising way to control cancer cell behavior.…”

New Pyrimido-Indole Compound CD-160130 Preferentially Inhibits the KV11.1B Isoform and Produces Antileukemic Effects without Cardiotoxicity

“…In these conditions, even 0.1 mM produced significant reduction of cell proliferation. This is also in agreement with recent results by Pier et al (2014) showing that nonsaturating concentrations of hERG1 blockers need to be applied for long periods of time to fully produce their antitransformation effects. Although different leukemia models and different administration schedules (e.g., twice per day) could be tested, our in vivo data indicate that CD-160130 is On the whole, K V 11.1 would seem an attractive target for antineoplastic therapy, particularly in leukemias.…”

Ion channels and transporters in metastasis

“…NIH3T3-cells stably transfected with K v 11.1 (hERG1) channels show a loss of cell contact inhibition. In culture, these cells grow in multiple layers and at high density [31]. Interestingly, their morphology changes from fibroblast-like to spindle-shaped while both the degree of cell polarization and migration increase.…”

“…Interestingly, their morphology changes from fibroblast-like to spindle-shaped while both the degree of cell polarization and migration increase. Furthermore, allogeneic transplantation of hERG1-expressing cells into nude mice leads to an increased incidence of tumors [31].…”