Novel roles for herg k+ channels in cell proliferation and apoptosis

ABSTRACT The human ether-a-go-go-related gene potassium channel (hERG, Kv11.1, KCNH2) has an essential role in cardiac action potential repolarization. Electrical dysfunction of the

voltage-sensitive ion channel is associated with potentially lethal ventricular arrhythmias in humans. hERG K+ channels are also expressed in a variety of cancer cells where they control

cell proliferation and apoptosis. In this review, we discuss molecular mechanisms of hERG-associated cell cycle regulation and cell death. In addition, the significance of hERG K+ channels

as future drug target in anticancer therapy is highlighted. SIMILAR CONTENT BEING VIEWED BY OTHERS MAPPING THE FUNCTIONAL EXPRESSION OF AUXILIARY SUBUNITS OF KCA1.1 IN GLIOBLASTOMA Article

Open access 20 December 2022 ROLE OF TRPM2 IN BRAIN TUMOURS AND POTENTIAL AS A DRUG TARGET Article 09 June 2021 KV1.3 VOLTAGE-GATED POTASSIUM CHANNELS LINK CELLULAR RESPIRATION TO

PROLIFERATION THROUGH A NON-CONDUCTING MECHANISM Article Open access 07 April 2021 ION CHANNELS INVOLVED IN CELL PROLIFERATION AND DEATH Ion channels have been implicated in signaling

pathways leading to cell proliferation or apoptosis (programmed cell death). Their identification and functional characterization in tumor cells suggest potential significance in anticancer

therapy. Transient receptor potential channels form a superfamily of ubiquitously expressed channels influencing the balance between cell survival and death.1, 2 In addition,

hyperpolarization-activated cyclic nucleotide-gated channels were detected in embryonic stem cells where they exert pro-proliferatory effects. Potassium channels represent the largest group

of channels involved in cell death and proliferation.3, 4 Calcium-activated KCa3.1 channels contribute to proliferation and atherosclerosis, and inhibition of the current attenuates fibrosis

and lymphocyte proliferation.5, 6, 7, 8 Furthermore, voltage-gated K+ channels (e.g. Kv1.3) or two-pore-domain channels (e.g. K2P5.1) determine growth of adenocarcinomas.9, 10

Voltage-sensitive human ether-a-go-go-related gene (hERG) potassium channels have recently emerged as novel regulators of growth and death in cancer cells. This review focuses on hERG

channels in proliferation and apoptosis. Current knowledge on expression, function and regulation is reviewed, and clinical implications are discussed. DIFFERENTIAL EXPRESSION OF HERG

POTASSIUM CHANNELS CARDIAC EXPRESSION AND FUNCTION OF HERG K+ CHANNELS. Repolarization of cardiac ventricular myocytes is mainly regulated by outward potassium currents. One of the most

important currents is the delayed rectifier potassium current, _I_K, which has rapidly and slowly activating components (_I_Kr and _I_Ks).11 Activation of the rapid component of the delayed

rectifier potassium current, _I_Kr, terminates the plateau phase and initiates repolarization of the cardiac action potential. The hERG encodes the voltage-gated potassium channel

_α_-subunit underlying _I_Kr.12, 13, 14 hERG potassium channels form homo-tetramers of identical six transmembrane spanning domains, with a cluster of positive charges localized in the S4

domain serving as voltage sensor. hERG channels are a primary target for the pharmacological management of arrhythmias with class III antiarrhythmic agents.15, 16 Blockade of hERG currents

causes lengthening of the cardiac action potential, which may produce a beneficial class III antiarrhythmic effect. Excessive reduction of HERG currents due to mutations in hERG or _via_

blockade produces chromosome-7-linked congenital long QT syndrome (LQTS-2) and acquired long QT syndrome, respectively. Both forms of LQTS are associated with delayed cardiac repolarization,

prolonged electrocardiographic QT intervals, and a risk for the development of ventricular ‘torsade de pointes’ arrhythmias and sudden cardiac death. hERG channels are inhibited by a

variety of non-antiarrhythmic compounds. This undesirable side effect is now considered a significant hurdle in the development of new and safer drugs, and has forced removal of several

drugs from the market. In addition to LQTS, cardiomyocyte apoptosis has been reported following pharmacological hERG K+ channel blockade.17 HERG K+ CHANNELS IN CANCER Various cancer cell

lines of epithelial, neuronal, leukemic, and connective tissue origin express hERG K+ channels (Table 1), whereas corresponding non-cancerous cells and cell lines do not exhibit significant

hERG protein levels. In corresponding human cancers, hERG protein may serve as biomarkers of malignant transition. Furthermore, hERG expression is implicated in enhanced cell proliferation,

invasiveness, lymph node dissemination, and reduced cell differentiation and prognosis.21, 22 In addition, increased neoangiogenesis, another hallmark of malignant tissue growth, has been

reported for glioblastoma where the generation of blood vessels was stimulated by hERG-dependent secretion of vascular endothelial growth factor.27 DIFFERENTIAL HERG EXPRESSION PATTERNS

DURING ONTOGENESIS. While hERG expression in normal adult human tissue is limited to heart, brain, myometrium, pancreas, and hematopoietic progenitors, other species have been described to

undergo changes in their ERG expression profile during ontogenesis: quail embryos express ERG K+ channels in peripheral ganglia and skeletal muscle in addition to heart and central nervous

system.47 This observation illustrates that hERG expression in tumor cells might either represent ectopic re-expression of a gene that remains silent in differentiated cells, or reflect

re-activation of embryonic genes, which is well recognized in cancers.35 CELL PROLIFERATION FUNCTIONAL ROLE OF HERG K+ CHANNELS IN CELL PROLIFERATION In differentiated adult cells, resting

membrane potential varies from −40 mV to about −90 mV.48 These distinct differences are closely correlated to the proliferative potential of respective cell types, ranging from slowly

proliferating or non-proliferative neurons or muscle cells (−70 mV to −90 mV) to highly proliferative glandular epithelia of liver, thyroid, pancreas, or salivary glands (−40 mV to −55 

mV).48 hERG K+ channels are closed at membrane potentials below a threshold of ∼−60 mV1 whereas classical inwardly rectifying channels remain open at more negative membrane potentials.49 The

predominance of hERG in cycling cells may thus account for the depolarized resting membrane potential in these cells.31 The membrane potential of cycling cells is particularly depolarized

during the G1 phase. However, K+ channel-dependent hyperpolarization appears to be critical for progression to the S phase. Hyperpolarization evokes Ca2+ influx, which is further augmented

by calcium-dependent K+ (KCa) channels and permits synthesis of mitogenic factors. In addition, hyperpolarization provides the electrical gradient necessary for Na+-dependent transport of

metabolic substrates and ions across the plasma membrane, which is required for DNA synthesis.50 Considering that K+ channels are involved in cell cycle progression, abundant expression of

K+ channels is expected to cause loss of proliferative control if endogenous pathways fail to block excessively expressed K+ channels.50 Interestingly, the promoter region of the hERG gene

harbors multiple binding sites for oncoproteins, such as specificity protein 1 and nuclear factor kappa light chain enhancer of activated B-cells, and for the tumor suppressor protein Nkx3.1

(Nk3 homeobox 1).30 We may hypothesize that mutations in oncoproteins constitutively activate hERG gene expression, shifting resting membrane potentials of cancerous cells toward more

depolarized values and repolarizing them at the end of G1 phase, thereby facilitating cell cycle progression and thus leading to cell proliferation. Here, pharmacological intervention using

hERG antagonists will serve to arrest the cell cycle in the G1 phase. Furthermore, human gastric cancer cells exhibit reduced levels of the regulatory _β_-subunit KCNE2, leading to hERG

current increase.51, 52 In addition, genetic deletion of KCNE2 is associated with gastric neoplasia and increased nuclear cyclin D1 levels in mice, revealing genetic manipulation of cell

proliferation mediated by a hERG _β_-subunit.52 Various cancer cell lines and cardiomyocytes have been reported to express an N terminally truncated splice variant of hERG, hERG1b, that

confers specific electrophysiological properties.53 Pharmacological approaches targeting the hERG1/hERG1b ratio may modulate the resting membrane potential of cycling cells. Increased hERG1b

levels are expected to depolarize cells, while high hERG1 levels will shift membrane potential toward more hyperpolarized values35 and suppress cell proliferation. HERG POTASSIUM CHANNEL

BLOCKERS MODULATE PROLIFERATION. Leukemic cell lines express hERG K+ channels whereas non-cancerous lymphocytes do not exhibit hERG protein. Selective hERG channel blockade by E-4031 reduced

proliferation in cancerous cell lines.25 Unspecific deceleration of the cell cycle and reduction of cell proliferation50 were ruled out in mechanistic analyses, confirming specific cell

cycle arrest as underlying mechanism. Cell cycle analysis of FLG29.1 leukemia cells revealed accumulation of cells in the G1 phase following treatment with hERG channel blockers.24

Furthermore, additional structurally different hERG blockers have been shown to achieve cell cycle arrest in G1 phase of hERG-positive cells (Table 2). It is noteworthy that the hERG blocker

erythromycin blocks cell cycle in G2 phase if administered together with vincristine.29 In addition, hERG blockers doxazosin and terazosin did not cause cell cycle arrest despite hERG

expression in distinct cell lines, for example, LNCaP prostate carcinoma cells.30, 57 SIGNIFICANCE OF HERG ION CHANNELS IN APOPTOSIS PROAPOPTOTIC EFFECTS OF HERG K+ CHANNEL INHIBITORS. hERG

channel blockers have been shown to induce apoptosis in different cell types. This mechanism is independent of their capacity to inhibit cell proliferation via cell cycle arrest. The

significance of hERG K+ channels in apoptotic pathways has been demonstrated in hERG-transfected HEK293 cells, which underwent apoptosis upon administration of doxazosin, compared with

control HEK293 cells lacking endogenous hERG.58 Doxazosin is an _α_1-adrenocepor antagonist with hERG-blocking properties that is clinically used as antihypertensive drug.59 In the

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which compared novel antihypertensive drugs to diuretic treatment in 33 000 patients, the doxazosin arm

had to be discontinued due to an increase in congestive heart failure that may be attributed to cardiomyocyte apoptosis.60, 61 The proapoptotic effect of doxazosin has been confirmed _in

vitro_ in the murine atrial tumor cell line HL-1 and in isolated adult human cardiomyocytes,17 providing a possible explanation for the increased incidence of congestive heart failure in the

doxazosin arm of the ALLHAT trial. In addition to hypertension, doxazosin is used for treatment of lower urinary tract symptoms caused by benign prostatic hyperplasia (BPH). Smooth muscle

relaxation due to _α_1-adrenergic blockade was initially thought to underlie the relief of symptoms in BPH patients. However, subsequent studies revealed an apoptotic effect of doxazosin in

hyperplastic prostatic tissue that may contribute to its clinical efficacy.62 Furthermore, doxazosin induced apoptosis in prostatic cancer cells.63 Limitations arise from the lack of studies

directly comparing hERG expression in normal, hyperplastic, and cancerous prostatic tissue, respectively. Finally, hERG channel expression is well documented in pituitary adenoma cells.45

When treated with doxazosin _in vitro_, antiproliferative and proapoptotic effects were observed in pituitary adenoma cells independent of antiadrenergic properties of the drug.55 MOLECULAR

MECHANISMS OF HERG-ASSOCIATED APOPTOSIS. hERG K+ channel blockers such as doxazosin activate multiple apoptotic pathways. However, evidence for a direct mechanistic link between hERG K+

channels and apoptotic proteins remains sparse to date. In HL-1 cardiomyocytes, doxazosin induces apoptosis via the endoplasmic reticulum pathway, involving enhanced phosphorylation of p38

mitogen-activated protein kinase, which activates GADD153/CHOP (growth arrest and DNA damage-induced gene 153/c/EBP homologous protein). GADD153/CHOP subsequently forms heterodimers with

DNA-binding protein c/EBP_β_ (CCAAT enhancer-binding protein beta) and translocates into the nucleus, where it augments transcription of the carbonic anhydrase DOC-1 (downstream of CHOP-1).

DOC-1 then acidifies intracellular pH and facilitates apoptosis.64 Finally, the CHOP pathway results in activation of a key apoptotic enzyme, caspase 3.65 Caspase activation by doxazosin

induces cleavage of the protein-tyrosine kinase FAK (focal adhesion kinase) in HL-1 cells, which compromises cell adhesion and leads to apoptosis.64 FAK is an essential component of integrin

signaling and is phosphorylated when cells are adhered to the extracellular matrix. Thus, it provides a survival signal and prevents apoptosis.66 In prostate cancer cells, FAK is cleaved by

caspase 3 upon treatment with doxazosin, which leads to apoptosis or anoikis (i.e. apoptosis due to loss of cell adhesion).67 Furthermore, hERG1, integrin _β_1, and FAK form a

macromolecular complex in hERG1-transfected HEK293 cells and SH-SY5Y neuroblastoma cells. Cell adhesion via integrin _β_1 causes activation of hERG1, which is essential for direct FAK

phosphorylation (Figure 1).37 FAK and hERG overexpression have independently been related to enhanced dissemination and invasiveness of tumors.20, 66 FAK phosphorylation due to hERG

activation may explain the ability of malignant cells to circumvent apoptosis once they have lost contact to the extracellular matrix. The abundant expression of hERG and FAK might provide

crucial survival signals in the absence of cell adhesion, and thus account for increased invasiveness and dissemination of hERG-positive tumors. In addition, colocalization with hERG

potassium channels activates the GTPase Rac1 and may contribute to adhesion-dependent modulation of tumor cell motility.37 Cell type- and environment-specific effects on apoptosis are

suggested by reports of hERG activity promoting apoptosis. In hERG-positive SKBr3, SH-SY5Y, and HL-1 cells, apoptosis occurs via a caspase 3-dependent pathway in response to extracellular

administration of H2O2 or TNF_α_ (tumor necrosis factor _α_), whereas selective inhibition of hERG conductance by dofetilide attenuates the proapoptotic effect of H2O2 and TNF_α_.33 The

methodology in the latter study is different from investigations mentioned above. Cells were first incubated with H2O2 or TNF_α_ to induce apoptosis, followed by application of hERG

blockers. In the same study, hERG is revealed to recruit TNF_α_ receptor 1 to the plasma membrane, which might explain increased responsiveness to TNF_α_ in these cells.33 The authors

describe a proliferative effect in hERG-expressing cells at low doses of TNF_α_ and an antiapoptotic effect of the hERG inhibitor dofetilide upon pretreatment with H2O2 and TNF_α_. These

observations appear to be at odds with proapoptotic effects of hERG K+ channel blockers. The hERG blocker doxazosin has been proven as a proapoptotic agent in a wide range of _in vitro_ and

_in vivo_ studies. Doxazosin increases the intracellular H2O2 content in BPH stromal cells. This is considered to facilitate TNF_α_-related pathways.68 Administration of H2O2 before hERG

inhibition appears to interfere with hERG-induced signaling pathways, which augment intracellular H2O2 levels. The antiapoptotic effect of hERG channel blockade may be due to this

interference. However, pro- and antiapoptotic effects of hERG blockers might coexist, and proapoptotic effects, including the increase in intracellular H2O2, could outweigh a possible

antiapoptotic effect through suppression of the apoptotic H2O2 – TNF_α_ pathway. However, an unambiguous differentiation between effects of hERG conductance and hERG expression is lacking,

and the mechanism by which hERG conductance facilitates H2O2- and TNF_α_-mediated apoptosis remains unclear at the molecular level. CLINICAL AND THERAPEUTIC IMPLICATIONS DIAGNOSTIC VALUE OF

HERG K+ CHANNEL EXPRESSION IN TUMORS hERG may be utilized as a potential tumor marker, given their expression in a variety of tumor cells and their absence from most non-cancerous human

tissues. Specifically, hERG was detected in endometrial cancer at mRNA (sensitivity=67%; _n_=18) and protein levels (sensitivity=82%; _n_=18), whereas only 18% (_n_=11) of non-cancerous

endometrial samples exhibited hERG mRNA or protein.23 In colon carcinomas, hERG mRNA was a more sensitive and more specific indicator for malignancy (100% sensitivity and specificity;

_n_=23) than mRNA of the established tumor markers CEA (sensitivity=94.4%; _n_=18), CK19 (sensitivity=77.8%; _n_=18), or CK20 (sensitivity=94.4%; _n_=18).18 Immunohistochemical staining for

hERG protein reached similar sensitivity and specificity as hERG mRNA.18 Further validation is required in larger patient populations. PROGNOSTIC SIGNIFICANCE OF HERG K+ CHANNEL EXPRESSION

IN TUMORS The prognostic value of hERG expression in tumors has been evaluated in several tissues. In acute myeloid leukemia (AML) blasts, hERG K+ channel expression is associated with a 50%

reduction of relapse-free and overall survival time compared with patients with hERG-negative AML (12 _versus_ 23 months).69 Patients with esophageal squamous cell carcinomas similarly

exhibit reduced survival (30 _versus_ 56 months) when hERG is detected.22 However, hERG K+ channel expression was not significantly associated with invasiveness, dissemination, or tumor

grade in this study. In gastric cancer cells, levels of hERG expression are positively correlated to tumor de-differentiation and TNM stage.21 Moreover, tumor growth was observed in BALB/c

nu/nu mice following injection of gastric cancer cells. Injection of cancer cells that were pretreated with hERG siRNA significantly attenuated tumorigenesis,21 confirming the pathological

significance of hERG in tumor growth and suggesting a potential novel target in anticancer therapy (see below). In colonic adenocarcinomas, there is a significant correlation between hERG K+

channel expression and invasiveness or dissemination. hERG is not detected in normal colonic mucosa (0%; _n_=60) and rarely observed in adenoma (9%; _n_=11). In contrast, substantial hERG

was found in patients with non-metastatic adenocarcinoma (75%; _n_=52) and metastatic adenocarcinoma (100%; _n_=8), with the most pronounced staining found in hepatic and peritoneal

metastasis.20 ANTICANCER THERAPY The antihypertensive _α_1-adrenoceptor blocker doxazosin is an established treatment option in BPH. Its therapeutic efficacy has been attributed to induction

of apoptosis in hyperplastic and cancerous prostate cells.57 Furthermore, hERG-positive cancer cells have been reported to be particularly susceptible to chemotherapeutics vincristine,

paclitaxel, and hydroxycamptothecin.29 Direct effects of vincristine, paclitaxel, and hydroxycamptothecin on hERG channels remain to be investigated. Erythromycin, a macrolide antibiotic

with hERG-blocking properties, further enhances the antiproliferative effect of these chemotherapeutics.29 The most intriguing perspective of anticancer therapy targeting hERG channels is

direct blockade of the potassium channel, which is expected to produce antiproliferative and proapoptotic effects that diminish tumor growth and invasiveness. The first proof of concept

study confirmed prevention of gastric cancer cell proliferation by the hERG K+ channel blocker cisapride.70 A systematic _in vivo_ investigation of chemotherapeutic properties and potential

cardiac side effects of hERG inhibitors is required. POTENTIAL SIDE EFFECTS AND LIMITATIONS OF ANTICANCER THERAPY BASED ON HERG CURRENT INHIBITION Proarrhythmic14 and cardiotoxic risks of

hERG inhibitors require careful evaluation7 when applying these compounds in clincial oncology. Systemic treatment of cancers with hERG antagonists may affect cardiac myocytes, resulting in

apoptosis and heart failure. In addition, application of hERG antagonists may induce QT prolongation and ventricular tachycardia. Although cancer treatment usually occurs in life-threatening

situations, and in some cases potential cardiac damage is accepted (e.g. during use of anthracyclines), optimal suppression of these events will be required. To prevent proarrhythmic side

effects, short-term drug application may be sufficient to induce apoptosis in tumor cells with minimal effects on cardiac electrophysiology. ECG monitoring should be performed during

application of the drug. Additional pharmacological inhibition of cardiac L-type calcium channels or _β_-adrenoceptors may offset the limiting proarrhythmic effects of hERG channel

inhibitors.71, 72, 73 Cardiomyocyte apoptosis may be circumvented through targeted delivery techniques such as direct injection or trans-arterial drug application. Gene therapy represents an

additional therapeutic approach to targeted suppression of hERG channel expression in cancers. Different proliferative states of cardiac and tumor cells may render cancerous tissue more

susceptible to pro-apoptotic and antiproliferative stimuli, reducing the overall risk of heart failure during systemic application of hERG antagonists. Feasibility of tumor-selective

hERG-based anticancer therapy will further depend on differential drug effects on cancerous and non-cancerous tissue expressing hERG K+ channels. CONCLUSION hERG potassium channels,

previously recognized to promote cardiac action potential repolarization, are now revealed to serve as regulators of proliferation and apoptosis in cancer cells. Their significance in

anticancer therapy is supported by mechanistic data and preliminary _in vivo_ studies. Limitations arise from potential cardiac side effects that require attention. Further studies are

warranted to provide a more complete understanding of hERG effects on apoptotic pathways. Downstream signaling proteins may serve as more specific therapeutic drug targets in future

anticancer therapy. ABBREVIATIONS * ALLHAT: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial * AML: acute myeloid leukemia * BPH: benign prostatic hyperplasia *

CHOP: c/EBP homologous protein * DOC-1: downstream of CHOP-1 * FAK, focal adhesion kinase∣hERG: human ether-a-go-go-related gene * Kv: voltage-gated potassium channel * LQTS: long QT

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ACKNOWLEDGEMENTS This study was supported in part by research grants from the ADUMED foundation (to DT), the German Heart Foundation/German Foundation of Heart Research (to DT), and the

Max-Planck-Society (TANDEM project to PAS). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Cardiology, Medical University Hospital, Heidelberg, Germany J Jehle, P A Schweizer, H

A Katus & D Thomas Authors * J Jehle View author publications You can also search for this author inPubMed Google Scholar * P A Schweizer View author publications You can also search

for this author inPubMed Google Scholar * H A Katus View author publications You can also search for this author inPubMed Google Scholar * D Thomas View author publications You can also

search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to D Thomas. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest.

ADDITIONAL INFORMATION Edited by V De Laurenzi RIGHTS AND PERMISSIONS This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To

view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Jehle, J., Schweizer, P., Katus, H. _et

al._ Novel roles for hERG K+ channels in cell proliferation and apoptosis. _Cell Death Dis_ 2, e193 (2011). https://doi.org/10.1038/cddis.2011.77 Download citation * Received: 20 May 2011 *

Revised: 14 July 2011 * Accepted: 18 July 2011 * Published: 18 August 2011 * Issue Date: August 2011 * DOI: https://doi.org/10.1038/cddis.2011.77 SHARE THIS ARTICLE Anyone you share the

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Nature SharedIt content-sharing initiative KEYWORDS * hERG * K+ channel * cell proliferation * apoptosis * anticancer therapy