Evidence map›Paper›PMID 24830940›Full record

ArticleMolecular pharmacology2014

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

David M Pier, George S G Shehatou, Susan Giblett, Christine E Pullar, Derek J Trezise, Catrin A Pritchard, R A John Challiss, John S Mitcheson

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
0.9field-weighted citation impact, top 27% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed, 11 citations in OpenAlex.

  1. Article
  2. Review
  3. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 5 institutions in 2 countries.

David M PierDepartment of Cell Physiology and Pharmacology (D.M.P., G.S.G.S., C.E.P., R.A.J.C., J.S.M.) and Department of Biochemistry (S.G., C.A.P.), University of Leicester, Leicester, United Kingdom; Molecular Discovery Research, GlaxoSmithKline R&D, Harlow, Essex, United Kingdom (D.J.T.); Department of Pharmacology and Toxicology, University of Mansoura, Egypt (G.S.G.S.); Essen Bioscience Ltd., Welwyn Garden City, UK (D.J.T.); School of Clinical Sciences, University of Edinburgh, United Kingdom (D.M.P.).
George S G ShehatouDepartment of Cell Physiology and Pharmacology (D.M.P., G.S.G.S., C.E.P., R.A.J.C., J.S.M.) and Department of Biochemistry (S.G., C.A.P.), University of Leicester, Leicester, United Kingdom; Molecular Discovery Research, GlaxoSmithKline R&D, Harlow, Essex, United Kingdom (D.J.T.); Department of Pharmacology and Toxicology, University of Mansoura, Egypt (G.S.G.S.); Essen Bioscience Ltd., Welwyn Garden City, UK (D.J.T.); School of Clinical Sciences, University of Edinburgh, United Kingdom (D.M.P.).
Susan GiblettDepartment of Cell Physiology and Pharmacology (D.M.P., G.S.G.S., C.E.P., R.A.J.C., J.S.M.) and Department of Biochemistry (S.G., C.A.P.), University of Leicester, Leicester, United Kingdom; Molecular Discovery Research, GlaxoSmithKline R&D, Harlow, Essex, United Kingdom (D.J.T.); Department of Pharmacology and Toxicology, University of Mansoura, Egypt (G.S.G.S.); Essen Bioscience Ltd., Welwyn Garden City, UK (D.J.T.); School of Clinical Sciences, University of Edinburgh, United Kingdom (D.M.P.).
Christine E PullarDepartment of Cell Physiology and Pharmacology (D.M.P., G.S.G.S., C.E.P., R.A.J.C., J.S.M.) and Department of Biochemistry (S.G., C.A.P.), University of Leicester, Leicester, United Kingdom; Molecular Discovery Research, GlaxoSmithKline R&D, Harlow, Essex, United Kingdom (D.J.T.); Department of Pharmacology and Toxicology, University of Mansoura, Egypt (G.S.G.S.); Essen Bioscience Ltd., Welwyn Garden City, UK (D.J.T.); School of Clinical Sciences, University of Edinburgh, United Kingdom (D.M.P.).
Derek J TreziseDepartment of Cell Physiology and Pharmacology (D.M.P., G.S.G.S., C.E.P., R.A.J.C., J.S.M.) and Department of Biochemistry (S.G., C.A.P.), University of Leicester, Leicester, United Kingdom; Molecular Discovery Research, GlaxoSmithKline R&D, Harlow, Essex, United Kingdom (D.J.T.); Department of Pharmacology and Toxicology, University of Mansoura, Egypt (G.S.G.S.); Essen Bioscience Ltd., Welwyn Garden City, UK (D.J.T.); School of Clinical Sciences, University of Edinburgh, United Kingdom (D.M.P.).
Catrin A PritchardDepartment of Cell Physiology and Pharmacology (D.M.P., G.S.G.S., C.E.P., R.A.J.C., J.S.M.) and Department of Biochemistry (S.G., C.A.P.), University of Leicester, Leicester, United Kingdom; Molecular Discovery Research, GlaxoSmithKline R&D, Harlow, Essex, United Kingdom (D.J.T.); Department of Pharmacology and Toxicology, University of Mansoura, Egypt (G.S.G.S.); Essen Bioscience Ltd., Welwyn Garden City, UK (D.J.T.); School of Clinical Sciences, University of Edinburgh, United Kingdom (D.M.P.).
R A John ChallissDepartment of Cell Physiology and Pharmacology (D.M.P., G.S.G.S., C.E.P., R.A.J.C., J.S.M.) and Department of Biochemistry (S.G., C.A.P.), University of Leicester, Leicester, United Kingdom; Molecular Discovery Research, GlaxoSmithKline R&D, Harlow, Essex, United Kingdom (D.J.T.); Department of Pharmacology and Toxicology, University of Mansoura, Egypt (G.S.G.S.); Essen Bioscience Ltd., Welwyn Garden City, UK (D.J.T.); School of Clinical Sciences, University of Edinburgh, United Kingdom (D.M.P.).
John S MitchesonDepartment of Cell Physiology and Pharmacology (D.M.P., G.S.G.S., C.E.P., R.A.J.C., J.S.M.) and Department of Biochemistry (S.G., C.A.P.), University of Leicester, Leicester, United Kingdom; Molecular Discovery Research, GlaxoSmithKline R&D, Harlow, Essex, United Kingdom (D.J.T.); Department of Pharmacology and Toxicology, University of Mansoura, Egypt (G.S.G.S.); Essen Bioscience Ltd., Welwyn Garden City, UK (D.J.T.); School of Clinical Sciences, University of Edinburgh, United Kingdom (D.M.P.) jm109@le.ac.uk.
University of Edinburgh · GBMolecular Discovery (United Kingdom) · GBGlaxoSmithKline (United Kingdom) · GBMansoura University · EGUniversity of Leicester · GB

Funding

Biotechnology and Biological Sciences Research CouncilMedical Research Council G0001361
6 · The paper itself

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 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.

Indexed as

ActinsAnimalsCell LineCell MovementCell ProliferationCell Transformation, NeoplasticEther-A-Go-Go Potassium ChannelsFibroblastsFocal AdhesionsHumansMiceMice, NudeNIH 3T3 CellsPotassium Channel BlockersStress FibersTransfectionActinsEther-A-Go-Go Potassium ChannelsPotassium Channel Blockers

Identifiers

PMID24830940
PMCPMC4127929
OpenAlexW2121659114

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.