Potassium channels: New targets in cancer therapy

Cancer Detection and Prevention 30 (2006) 375–385 www.elsevier.com/locate/cdp

Potassium channels: New targets in cancer therapy Antonio Felipe PhDa,*, Rube´n Vicente PhDa, Nu´ria Villalonga MSca, Meritxell Roura-Ferrer BSca, Ramo´n Martı´nez-Ma´rmol BSca, Laura Sole´ BSca, Joan C. Ferreres MDb, Enric Condom MDc a

Molecular Physiology Laboratory, Departament de Bioquı´mica i Biologia Molecular, Facultat de Biologı´a, Universitat de Barcelona, Avda. Diagonal 645, E-08028, Barcelona, Spain b Departament de Anatomı´a Patolo`gica, Hospital Universitari Vall d’Hebron, Barcelona, Spain c Departament de Patologia I Terape`utica Experimental, Hospital Universitari de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain Accepted 26 June 2006

Abstract Background: Potassium channels (KCh) are the most diverse and ubiquitous class of ion channels. KCh control membrane potential and contribute to nerve and cardiac action potentials and neurotransmitter release. KCh are also involved in insulin release, differentiation, activation, proliferation, apoptosis, and several other physiological functions. The aim of this review is to provide an updated overview of the KCh role during the cell growth. Their potential use as pharmacological targets in cancer therapies is also discussed. Methods: We searched PubMed (up to 2005) and identified relevant articles. Reprints were mainly obtained by on line subscription. Additional sources were identified through cross-referencing and obtained from Library services. Results: KCh are responsible for some neurological and cardiovascular diseases and for a new medical discipline, channelopathies. Their role in congenital deafness, multiple sclerosis, episodic ataxia, LQT syndrome and diabetes has been proven. Furthermore, a large body of information suggests that KCh play a role in the cell cycle progression, and it is now accepted that cells require KCh to proliferate. Thus, KCh expression has been studied in a number of tumours and cancer cells. Conclusions: Cancer is far from being considered a channelopathy. However, it seems appropriate to take into account the involvement of KCh in cancer progression and pathology when developing new strategies for cancer therapy. # 2006 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved. Keywords: Cancer; Potassium channels; Gene therapy; Cell proliferation; Molecular-targeted therapies; Therapeutic targets; Pharmacological targets; Channelopathies; Cancer progression; Tumor markers; Cancer detection; Membrane proteins; Transduction pathways; Cell cycle control; G1/S transition; G2 phase; CDK inhibitors; Lymphocyte activation

1. Introduction Cancer is a multifactor process that involves several temporal steps. Cells first acquire a phenotype through the altered expression of proteins and genes. Afterwards, tumour cells proliferate massively and do not undergo apoptosis. Chemotherapy and radiosensitization have been widely used to block this progression. However, the use of these therapies is not synonymous with success. Nucleoside analogues have been widely used as a first attempt to control the cell cycle. These molecules are taken up by the cells by means of membrane * Corresponding author. Tel.: +34 934034616; fax: +34 934021559. E-mail address: [email protected] (A. Felipe).

transport systems. Nucleoside derivatives (i.e. fludarabine or gemcitabine, among others) used in cancer and antiviral therapies interfere with nucleoside metabolism and DNA replication, thus inducing their pharmacological effects [1]. In fact, nucleoside uptake is induced during proliferation. The inhibition of nucleoside transport systems by nucleoside derivatives arrests the cell cycle in the S phase [2–5]. Several nucleoside carriers have been described and molecularly characterized. Their activities overlap and their expression depends on the tissue and the differentiation status of the cell [5,6]. Although a lot of effort is involved in designing individual treatments, most current strategies are not selective. They may be harmful and are sometimes unsuccessful. In some cases, this lack of efficiency could be explained by tumour cells’

0361-090X/$30.00 # 2006 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.cdp.2006.06.002

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extraordinary ability to develop a multidrug resistance (MDR) phenotype in response to chemotherapy [7,8]. Thus, adaptive regulation, overlapped transport activities and their expression are the main obstacles in cancer therapeutics. Novel technologies such as genomics and proteomics have increased the number of human genes known to be differentially expressed in normal and malignant tissues. We have entered a new era, leaving cytotoxic approaches behind to focus on mechanisms based on gene therapy and pharmacogenomics. This new perspective has produced a large body of evidence indicating that KCh could play a relevant role in cancer therapy. Targeting potassium channels for cancer therapy could give rise to successful strategies for the following reasons: i) KCh are involved in cell proliferation as they control cell cycle progression. ii) KCh show cell and tissue-specific expression. iii) These proteins are highly sensitive to synthetic blockers and natural peptides, leading pharmaceutical companies to design more effective and selective molecules. iv) Current therapies for nerve and cardiac diseases successfully target KCh and have few side effects. v) Impaired expression of KCh has been detected in a number of cancer and tumour cells. In addition, overexpression of KCh has been described in some MDR cell lines and K+ channels effectors may partially reverse the MDR phenotype [7]. Furthermore, KCh control upstream nucleoside derivative uptake pathways [9]. Therefore, a combination of therapies involving chemotherapeutic agents and K+ channels blockers has been proposed.

2. Methods The criteria for the data selection in this review were the evidences obtained through an electronic data base search in PubMed of literature mainly published in the last 8 years (1998–2005). In addition, approximately one-fourth of the references were from the last two years. Only relevant papers prior to these dates were also considered. The searches were limited to articles published in English. Various combinations were searched using the keywords ‘‘potassium channels’’, ‘‘cancer’’, ‘‘cell growth’’, ‘‘proliferation’’ and ‘‘tumour’’ to scan titles, abstracts, and subject headings in data bases. This review also includes results from our laboratory.

3. Results 3.1. Criteria for the selection of studies Because the aim of this review is to highlight the involvement of potassium channels in cancer progression and pathology, studies were selected for citing based on their

relevance to this purpose. The evidences may also suggest that these proteins can be used as tumour markers in cancer detection. In addition, the latest literature indicates that the time has come to consider potassium channels when developing new strategies for cancer therapy. The information has been summarized descriptively in three main parts. First, a brief description of this large superfamily of membrane proteins, followed by evidences describing that K+ channels are involved in the cell cycle progression. Finally, information is given concerning the most relevant impaired K+ channel expression in tumours and cancer cells. 3.2. Potassium channels Potassium channels are one of the most diverse classes of membrane proteins. They have more than 75 different genes. KCh conduct the flux of potassium ions through the membranes of virtually all-living cells and generate either inward or outward currents. For an exhaustive description of their activities and structures, refer to the classical handbook on ion channels by Hille [10]. According to the IUPHAR compendium (http://www.iuphar-db.org/iuphar-ic/ionChannel.html) they are distributed in four superfamilies. Kv (Kv1 to Kv12) families are voltage-dependent; KCa (KCa1–5) families are Ca-dependent; K2p (K2p1–7, 9, 10, 12, 13, 15– 18) families are members of the two-pore domain group; and Kir (Kir1–7) isoforms show inward rectification. In addition to these pore-forming subunits, KCh channel diversity could be enhanced by the formation of oligomers with auxiliary subunits [11]. Before continuing, we will provide a brief description of each family’s members. These include either conducting (Table 1) or auxiliary (Table 2) subunits that are related to several inherited human diseases. This is just a summary of an increasing list of human disorders. Kv and KCa families mainly posses six transmembrane domains and may be further subdivided into seven conserved gene families. These comprise the voltage-dependent channels Kv1–4 (Shaker, Shab, Shaw, Shal-like subunits), the namely KCNQ channels (Kv7), the silent Kv5, Kv6, Kv8 and Kv9 subunits (modulators), the eag-like (Kv10–12) and three kinds of Ca2+ activated K+ channels KCa1 (BK, slo), KCa2 (SK) and KCa3 (IK). The Kv, KCNQ and eag-like K+ channels are typically closed at the resting potential of the cell, but open on membrane depolarization. They are involved in the repolarization of the action potential, and thus in the electrical excitability of nerve and muscle. They also modulate both synaptic transmission, activation (leukocytes), differentiation (myocytes) and secretion from endocrine cells (pancreatic b-cells). While mutations in the genes encoding members of these Kv channel subfamilies clearly lead to a number of human diseases, such as episodic ataxia, long QT syndrome and epilepsy, the contribution of KCa channels to myotonic dystrophy is not clear. Two other unrelated K+ channel groups are the two-pore domain (K2P) and the inward rectifier (Kir) families with four and two transmembrane domains, respectively. The

Table 1 The potassium channel classification system; HUGO and IUPHAR nomenclatures; structure and activity Members

HUGO nomenclature

Other aliases

Inherited disorders

Proteins involved

References

Activity

Structure

Voltage-dependent Kv1

Kv1.1-Kv1.7

KCNA1-KCNA7

Shaker-related1

Kv1.1

[57]

Outward-rectifying

6TM/1P

Kv2 Kv3 Kv4 Kv5 Kv6 Kv7

Kv2.1-Kv2.2 Kv3.1-Kv3.3 Kv4.1-Kv4.3 Kv5.1 Kv6.1-Kv6.3 Kv7.1-Kv7.5

KCNB1-KCNB2 KCNC1-3 KCND1-3 KCNF1 KCNG1-KCNG3 KCNQ1-KCNQ5

Shab-related2 Shal-related 3 Shaw-related4

Kv7.1

[58–63]

Outward-rectifying Outward-rectifying Outward-rectifying Modulatory Modulatory Outward-rectifying

6TM/1P 6TM/1P 6TM/1P 6TM/1P 6TM/1P 6TM/1P

Kv7.2

[64]

Kv7.3

[65]

Kv7.4

[66]

Modulatory Modulatory Outward-rectifying Outward-rectifying

6TM/1P 6TM/1P 6TM/1P 6TM/1P

Outward-rectifying

6TM/1P

Kv8 Kv9 Kv10 Kv11

Kv8.1 Kv9.1-Kv9.3 Kv10.1-Kv10.2 Kv11.1-Kv11.3

KCNB3 KCNS1-KCNS3 KCNH1; KCNH5 KCNH2

Eag-1; eag-2 Erg-1;erg-2; erg-3

Kv12

Kv12.1-Kv12.3

KCNH3; KCNH14

Elk-1;elk-2;elk-3

Myokimia with periodic ataxia, episodic ataxia (EAM, EA1) Unknown Unknown Unknown Unknown Unknown Long QT syndrome type 1 (LQT1, WardRomano syndrome). Jervell and Lange Nielsen syndrome Epilepsy, benign neonatal type 1 (EBN1, BFNC1) Epilepsy, benign neonatal type 2 (EBN2, BFNC2) Deafness, autosomal dominant type 2 (DFNA2) Unknown Unknown Unknown Long QT syndrome type 1 (LQT2) Unknown

Calcium-dependent KCa1 KCa2 KCa3

KCa1.1 KCa2.1-KCa2-3 KCa3.1

KCNMA1 KCNN1-KCNN3 KCNN4

Slo SKCa1-SKCa-3 IKCa1

Unknown Unknown Unknown

Maxi-KCa Slow-KCa Intermediate-KCa

7TM/1P 6TM/1P 6TM/1P

K2p1.1; K2p6.1; K2p7.1; K2p18.1 K2p2.1; K2p4.1; K2p5.1; K2p10.1; K2p16.1; K2p17.1 K2p3.1; K2p9.1; K2p15.1 K2p4.1-K2p17.1

KCNK1; KCNK6; KCNK7; KCNK18 KCNK2; KCNK4; KCNK5; KCNK10; KCNK16; KCNK17

TWIK1; TWIK2; TWIK3; TRESK-1 TREK1; TRAAK; TASK2; TREK2; TALK1; (TASK4, TALK2) TASK1; TASK3; TASK5 THIK1; THIK2

Unknown

Outward and inward-rectifying Outward-rectifying

4TM/2P

Outward-rectifying, Acid-sensitive Inward-rectifying, halothane-inhibited

4TM/2P

Two pore K2p1; K2p6; K2p7; K2p18 K2p2; K2p4; K2p5; K2p10; K2p16; K2p17 K2p3; K2p9; K2p15 K2p12-K2p13

KCNK3; KCNK9; KCNK15 KCNK12; KCNK13;

KvLQT1-5

Unknown

Unknown Unknown

Kv1 1.1

[67]

A. Felipe et al. / Cancer Detection and Prevention 30 (2006) 375–385

IUPHAR

4TM/2P

4TM/2P 377

Kir3.1-Kir3.4; Kir6.1-Kir6.2 Kir3; Kir6

Kir2; Kir5

Human inherited disorders associated with known mutations of genes encoding pore-forming (alpha) subunits of K+ channels are indicated. IUPHAR, the International Union of Pharmacology (http://www.iuphardb.org/iuphar-ic/ionChannel.html). HUGO (KCN nomenclature) was developed by the Human Genome Organisation in 1997 (http://www.gene.ucl.ac.uk/nomenclature/) and is continuously updated. Columns: IUPHAR, accepted nomenclature for each family; members, number of K+ channels in each family; HUGO, former Human Genome Organization nomenclature. These names are still valid for genes; Other aliases, some other names are mentioned for reference; inherited disorders, human diseases associated with known mutations; proteins involved, isoforms associated with these inherited disorders; activity, the most classical characteristic of their function; structure, TM indicates the number of transmembrane domains and P the number of pore segments in the protein. Other aliases: 1Shaker-related; 2Shab-related; 3Shal-related; 4Shawrelated, as prior to HUGO or IUPHAR nomenclature each member could have more than four other names. Only the Drosophila melanogaster relation is indicated.

2T/1P Inward-rectifying, ATP-sensitive [70,71] Persistent hyperinsulinaemic, hypoglycaemia of infancy, PHH1 GIRK1;GIRK2; GIRK3; GIRK 4; KATP1; BIR

Kir6.2

2T/1P Kir2.1 Andersen-Tawil syndrome

[69]

Inward-rectifying, ATP-regulated Inward-rectifying, strong rectification [68] Kir1.1 Bartter syndrome

KCNJ1; KCNJ10; KCNJ15; KCNJ13 KCNJ2; KCNJ4; KCNJ12; KCNJ14; KCNJ16 KCNJ3; KCNJ6; KCNJ9; KCNJ5; KCNJ8; KCNJ11 Kir1.1; Kir4.1; Kir4.2; Kir7.1 Kir2.1-Kir2.4; Kir5.1

ROMK, Kir1.2, Kir1.4 IKR1; IKR2; IRK2; IRK4;

Activity References Proteins involved Inherited disorders Other aliases HUGO nomenclature Members

Inward rectifiers Kir1; Kir4; Kir7

IUPHAR

Table 1 (Continued )

2T/1P

A. Felipe et al. / Cancer Detection and Prevention 30 (2006) 375–385 Structure

378

K2P channel family is structurally unique in that each subunit possesses two pore-forming domains and four transmembrane segments. These channels have properties of leak K+ channels, and therefore play a crucial role in setting the resting membrane potential and regulating cell excitability. Their activity can be modulated by polyunsaturated fatty acids, pH and oxygen, and some are candidate targets of volatile anaesthetics. In addition, K2P K+ channels are involved in cell apoptosis and tumorigenesis. However, despite their potential as targets for novel drugs for human health, little is known about the molecular basis of their diverse physiological and pharmacological properties. Inwardly rectifying K+ (Kir) channels show the property of inward rectification, an inward current evoked by hyperpolarizations from the potassium equilibrium potential. Kir channels regulate the membrane potential and are involved in K+ transport across membranes. They control cell differentiation, modulate neurotransmitter release, may act as hypoxia-sensors and regulate cerebral artery dilatation. In addition, these channels are important in the regulation of insulin secretion, proliferation and the control of vascular smooth muscle tone. Mutations in Kir channels trigger neuronal degeneration, failure of renal salt absortion and defective insulin secretion. Thus, in humans, persistent hyperinsulinemic hypoglycemia of infancy, a disorder affecting the function of pancreatic b cells, and Bartter’s syndrome, characterized by hypokalemic alkalosis, hypercalciuria, increased serum aldosterone, and plasma renin activity, are the two major diseases linked so far to mutations in a Kir channel or associated protein. In general, pore-forming potassium channel subunits form tetramers. Thus, in addition to functional diversity associated with auxiliary subunits, functional complexes can be generated by heterotetrameric complexes. These structures may be engendered by different members of the same or related (modulatory Kv) family. This complexity gives rise to KCh proteins’ diverse functional and pharmacological properties. KCh may play a number of functional roles through these mechanisms, which fine tunes their activity in the cell physiology [10]. 3.3. Potassium channels and cell proliferation Pharmacological tools have opened the way to understanding the role of K+ channels in cell proliferation. Experimental evidence in cellular physiology and pharmacology demonstrates that KCh are involved in the proliferation of normal and tumour cells. The physiological role of K+ channels in cell growth has been confirmed by a number of experiments. In such experiments the number of normal or tumour cells diminished when K+ channels were blocked with toxins or drugs. In 1996, Wonderlin and Strobl published a complete paper that addressed this point [12]. Since then, the list of drugs which demonstrate that pharmacological blockage of KCh inhibits cell proliferation has increased considerably. Further contributions have recently addressed

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379

Table 2 Potassium channel modulatory subunits IUPHAR name

Members

Other aliases

a Subunit partner

Inherited disorders

Kvb1.1-Kvb1.3 Kvb2.1 Kvb3-Kvb4 KCNE1

Kvb1, Kvb3 Kvb2 Kvb3 Mink, IsK,

Kv1 Kv1 Kv1 Kv7.1, Kv11.1

KCNE2

KCNE2

MiRP1

Kv11.1

KCNE3

KCNE3

MiRP2

Kv7.1; Kv7.4; Kv11.1; Kv3.4

KCNE4

KCNE4

MiRP3

KCNE5 KCHAP KCNIP

KCNE5 KCHAP KCNIP 1-KCNIP4

KCNE1L

Kv7.1; Kv1.1; Kv1.3; HCN4 Unknown Kv1.3; Kv2.1; Kv4.3 Kv4.1; Kv4.2; Kv4.3

Unknown Unknown Unknown Long QT syndrome type 5 (LQT5) JervellLange-Nielsen 2 Long QT syndrome type 6 (LQT6) Hyperkalemic periodic paralysis thyrotoxic hypokalemic periodic paralysis Unknown Alport syndrome Unknown Unknown

[75]

KCNMB1 KCNMB2 KCNMB3

Slo-beta

KCNMA1 KCNMA1 KCNMA1

Diastolic hypertension Unknown Unknown

[76]

KCNMB4

KCNMB1 KCNMB2 KCNMB3aKCNMB3d KCNMB4

KCNMA1

Unknown

ABCC8

ABCC8

SUR1,MRP8, PHHI

Kir6.1, Kir6.2

ABCC9

ABCC9A-ABCC9B

SUR2

Kir6.1, Kir6.2

Persistent hyperinsulinaemic, hypoglycaemia of infancy (PHH1), diabetes mellitus II Dilated cardiomyopathy

HUGO nomenclature

Voltage-dependent Kvb1 KCNAB1 Kvb2 KCNAB2 Kvb3 KCNAB3 KCNE1

KCHIP1-4

References

[72]

[72] [73,74]

Calcium-dependent

Inward rectifiers [70]

[77] +

HUGO and IUPHAR nomenclatures. Human inherited disorders associated with known mutations of genes encoding auxiliary beta subunits of K channels are indicated. IUPHAR, the International Union of Pharmacology (http://www.iuphar-db.org/iuphar-ic/ionChannel.html.) HUGO (KCN nomenclature) was developed by the Human Genome Organisation in 1997 (http://www.gene.ucl.ac.uk/nomenclature/) and is continuously updated. Columns: IUPHAR, accepted nomenclature for each gene family; members, number of K+ channels in each family; HUGO, former Human Genome Organization nomenclature. These names are still valid for genes; other aliases, some other names are mentioned for reference; a subunit partner, pore-forming subunit whose association has been certified. Inherited disorders, human diseases associated with known mutations.

the increasing list of models in which KCh are involved in cell growth [7,13,14]. To avoid repeating these articles we will go on to discuss why KCh may control cell cycle progression and proliferation. Direct evidence of KCh’s crucial role in proliferation has been obtained from studies of leukocytes [14–19]. The activity of these proteins is important during the G1/S transition. However, not all of the isoforms seem to act at the same time. Thus, it has been stated that KCh may be important in the early stages of G1, during the G1/S transition and even during the G2 phase (Fig. 1). The concentration of channel blocker needed to inhibit cell growth is sometimes higher than IC50 for the activity. This means that some undesirable side effects may be unrelated to KCh activity. However, some channels have been unequivocally shown to be required for cellular proliferation during cell growth in many cell types. This is the case for Kv1.3 in immune system cells [15,16,20]. Studies performed in heterologous expression systems suggest that while the presence of Kv1.3 promotes cell proliferation, the overexpression of Kv1.6 attenuates cell growth [21].

No direct evidence of the mechanism has been provided. However, the use of pharmacological tools suggests that the control of KCh may involve some CDK inhibitors such as p21 and p27 [22]. In oligodendrocyte proliferation, the incubation of cells in the presence of non-specific drugs and toxins induced the expression of both these inhibitors. This led to a blockage in the cell cycle progression, caused by a decrease in cyclins A and D [23]. There are several hypotheses that could explain the KCh control of the cell cycle. The soundest of these involves Ca2+ signaling. Calcium is important in cell physiology. Certain thresholds are crucial to promoting or inhibiting several signal transduction pathways [24]. During lymphocyte proliferation, it has been shown that induction of KCh triggers enough hyperpolarization to promote the exit of Ca2+ from internal reservoirs and to activate plasma membrane Ca2+ channels (CRAC channels) [25]. The CRAC channels are voltageindependent, so they do not close at hyperpolarising membrane potentials as normal voltage-gated Ca2+ channels do and exhibit a pronounced inward rectification, which promotes

380

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Fig. 1. Potassium channel blockers inhibit cell proliferation. Different toxins and compounds halt the cell cycle at different phases, leading to a decrease in cell growth. Although many drugs, toxins and compounds inhibit cell proliferation, only those that have been unequivocally documented are shown. Note that: (i) different channel subfamilies are involved in different phases; (ii) members of the Kv family (particularly Kv1) play a role during either the G1 or G1/S check point; (iii) charybdotoxin block KCa (KCa3.1) and Kv (Kv1.3), thus inhibiting the cell cycle by arresting cells in two different phases. TEA: tetraethylammonium; 4-AP: 4-aminopyridine; TEBuA: tetrabutylammonium; TEHeA: tetrahexylammonium; TEPeA: tetrapentylammonium. References are in parenthesis.

Ca2+ influx from the extracellular medium. This intracellular rise in Ca2+ initiates appropriate signalling, leading to lymphocyte activation and proliferation. Intracellular Ca2+ activates calcineurin leading to NF-AT (nuclear factor of activated T cells) dephosphorylation. NF-ATaccumulates into the nucleus and binds to the promoter element of the interleukin 2 gene (IL-2) triggering IL-2 production and T-cell activation [25]. Three types of KCh are involved in this process in immune system cells: Ca2+ dependent K+ channels (KCa3.1); voltage-dependent K+ channels (Kv1.3) and inward rectifier potassium channels (Kir2.1), [7,12,13,15,16,24–28]. Some studies demonstrate that proliferation is attenuated by inhibitors of the three proteins: charybdotoxin, clotrimazole or TRAM-34 for KCa3.1 [27,29,30]; charybdotoxin or margatoxin for Kv1.3 [16,25,31]; and divalent cations for Kir2.1 [16,32,33]. In fact, margatoxin and barium are additive, indicating that both channels are involved in the process in macrophages [16]. A sequential mechanism involving Kv and Kir channels during myoblast differentiation has also been proposed [34,35]. Authors suggest that after moderate hyperpolarization by Kv of around 30 to 40 mV, Kir2.1 channels strongly hyperpolarize the cell to almost K+ equilibrium potential values. This leads to the induction of T-type Ca channels, generating a window current that promotes myotubular fusion. The fact that several Kv genes are closely regulated during this process is in agreement with this hypothesis [36,37]. On the other hand, experimental evidence indicates that several membrane potential changes occur during cell growth. Highly proliferating cells are more depolarized than normal or quiescent cells [38–40]. This is an intriguing

situation, as KCh mostly generate hyperpolarization by extrusion of K+ from the cell. However, during the first phases of the cell cycle – G1 or G1/S transition – partial hyperpolarization as a result of KCh, and Kv in particular, may be needed [13,24]. A rational explanation would be that KCh are needed to control a specific check point during these stages. Proliferation also involves changes in the cell size and KCh may be involved contributing to the regulatory volume control during the cell cycle. Several studies indicate that KCh contribute to cell volume control [41,42]. This is because KCh are involved in K+ transport across the cell membrane, and ion movements, mainly K+ and Cl , are related to water homeostasis. In fact, a relation between KCh and aquaporin expression has been pointed out during cell differentiation [43,44]. Inhibition of KCh by blockers such as TEA, 4-AP and Cs+ increased cell volume and decreased the rate of cell proliferation [41,42]. However, this scenario highlights some apparent contradictions. Proliferation and apoptosis are opposite events but both involve KCh activation. Whilst experimental data indicate that proliferation is fully inhibited when cell volume increases, cell shrinkage is one of the hallmarks of apoptosis. Intracellular K+ and Cl efflux accompanying water efflux and cell shrinkage triggers a reduction in cytosolic K+ and relief of apoptotic inhibition. This loss of intracellular ions also plays a primary role in caspase activation and nuclease activity during apoptosis. These evidences lead researches to suggest a dual role for KCh during cell growth and apoptotic death. In this context, whilst macrophage proliferation activates Kv1.3 and

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Kir2.1 channels, LPS- and TNF-a-induced activation, both triggering apoptosis, increases Kv1.3 and abrogates Kir2.1 [16,17]. In summary, there is no clear consensus as to where KCh exert their specific control on cell cycle progression. However, the bottom line is that the pharmacological treatment of cells with KCh inhibitors impairs cell growth. 3.4. Potassium channels in tumour and cancer cells Besides the role of KCh during cell growth, highly proliferating cancer cells either up- or down-regulate KCh. Furthermore, the expression of KCh is impaired in several types of tumours. It has been demonstrated that a certain grade of malignancy correlates with the expression of KCh. Although several types of KCh have been associated with a highly proliferative state only a few types have clearly oncogenic effects. Thus, only Kv10.1 and K2p9.1 generate oncogenic phenotypes when introduced in healthy animals [45–47]. Altered expression of members from all groups of KCh has been found in different types of tumours and cancer cells. Whilst Kv1.3 is the most documented of the Kv1 (Shaker)

381

family and it is overexpressed in breast, colon and prostate cancer, Kv1.1 and Kv1.5 show impaired expression in breast and glioma malignant cell lines, respectively. Recently, an increase of Kv7.1 (KCNQ1) and KCNE1 subunits has been detected in germinal tumours [43]. Besides the oncogenic properties of Kv10.1 (see above), members from Kv10 (eag) and Kv11 (erg) families are expressed in a number of tumour and cancer cell lines. Thus, Kv10.1–2 were expressed in breast and neuroblastoma cancer and Kv11.1 has been detected in gastrointestinal, endometrial, neuroblastoma and leukemic cancer and cell lines. In addition, several inwardrectifier potassium channels (Kir) have been also detected in tumours. An increase of Kir proteins has been described in breast and lung cancers. However, in glioma, whilst Kir2.1 expression is inversely correlated with malignancy, an increased expression of Kir4.1 has been documented. The expression of KCa1.1 (BK) and KCa3.1 (IK) is also abundant in neuroblastoma and prostate cancer. Finally, altered expression of K2p9.1 has been observed in breast and lung cancers which correlate with malignancy in cell lines. Two factors may be involved in the impaired expression and role of KCh during cancer: cytokines and dedifferentiation. Studies in animal models have shown that several

Table 3 Ion channels and cancer Channel

Tumour

Characteristics

Expression

References

Kv1.1 Kv1.3

Breast Breast

Marked expression in cell lines Breast cancer samples and derived cell lines. While minoxidil, a channel opener, stimulates growth, aminodarone inhibits MCF-7 proliferation Colon specimens and cell lines. Channel openers increase cell growth while blockers inhibit cell proliferation Prostate biopsies and cell lines. Openers increase PC3 proliferation whereas blockers inhibit growth Inverse correlation with malignancy (astrocytoma, oligodendroglioma and glioblastoma) 4-aminopyridine and oligonucleotide antisense inhibit cell growth

+ +

[78] [79]

+

[80]

+

[81]

Colon Prostate Kv1.5

Glioma

Kv3.4 Kv7.1

Oral squamous cell carcinoma Germinal

Kv10.1-2

Breast Glioma

Kv11.1

Kir3.1 Kir4.1 KCa1.1 KCa3.1

Colon Endometrial cancer Glioma Leukaemia Glioma Lung Breast Glioma Glioma Prostate

K2p9.1

Breast

Kir2.1

Lung

Seminoma samples characterized by undifferentiated germ cells. The auxiliary subunit KCNE1 is also markedly increased hEAG expression induces cancer progression in a number of human cancer cell lines Marker expression in neuroblastoma cell lines. Oligonucleotides antisense inhibit cell proliferation Colorectal cancer cell lines. High correlation with invasive phenotype Marked expression compared with non-cancerous tissues Expression in neuroblastoma cell lines Constitutively present in leukemic cell lines. Blockers inhibit cell proliferation Inverse correlation with malignancy Marked expression in cell lines Correlation with breast cancer specimens and cell lines Proliferating cells. Tumours and glioma cell lines. Iberiotoxin inhibits cell migration Channel openers increase cell growth while blockers (charybdotoxin) inhibit cell proliferation Marked correlation with breast cancer tumours. Overexpression in cell lines promotes tumour formation Induction in a number of lung tumours

[82] +

[83,84]

+

[43]

+

[47]

+

[85,86]

+ +

[87] [88]

+ + + + + + +

[89,90] [91,92] [93,94] [33] [95–97] [98] [99–101] [102]

+

[45]

+

[46]

Channel, protein involved or studied; tumour, kind of tumour or cell origin; characteristics, main features observed; expression, (+) induced, ( ) diminished.

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cytokines, including tumour necrosis factor-a (TNF-a), interleukin-1 (IL-1), IL-6 and interferon-g (IFN-g), among others, can produce signs, symptoms and biochemical features that are commonly observed during cancer [48]. Functionally, cytokines are classified as either pro-inflammatory or anti-inflammatory. These compounds may act synergistically, or counteract, resulting in an effect that is significantly different to the sum of the individual effect. Cytokines exhibit pleiotropy and redundancy. Thus some functions can be mimicked in part by other cytokines [49]. These features have been partially demonstrated in the case of TNF-a [48]. As a result of a systemic inflammatory response, KCh expression may be regulated by TNF-adependent and independent mechanisms [16,17,50,51]. Clinical studies have demonstrated elevated circulating TNF-a levels in cancer patients as well as in other inflammatory diseases [52]. This cytokine is generated by leukocytes in response to an insult, such as an infection, AIDS or cancer [48,52]. However, while the expression of KCh may be increased in tumours, these proteins are downregulated in other tissues under this systemic response [50,51]. A rational explanation could be given on the basis of the balance of pro- and anti-apoptotic cytokines that may also contribute to different cellular responses [49]. Another conflictive issue could be raised as a result of the cellular dedifferentiation generated by cell growth. As a result of a neoplastic process, cells proliferate but concomitantly become dedifferentiated. These two processes are related and the interpretation of data is difficult. Recently, an increasing amount of evidence has been obtained [53–55]. Currently, there is no broad consensus on the role of KCh in cancer. However, evidence that tumour cell invasion can be handicapped by the use of channel blockers points towards the involvement of KCh in cancer progression and pathology. A summary of the data collected to date for neoplastic cells and tumours is presented in Table 3. These are just a few examples from an ever-growing list.

4. Conclusions Potassium channels in cell membranes regulate cellular excitability and proliferation. The central role of these ion channels in cell function has made them the target of several channelopathies. In light of the increasing amount of evidence showing that KCh are involved in cell proliferation and tumour growth, it seems that these proteins could be considered a pharmacological tool during cancer progression and pathology. The persistence of the MDR phenotype handicaps the treatment and the successful use of chemotherapy and radiosensitivity. Therefore, novel strategies based on a new post-genomic era should be considered. In fact, the use of KCh proteins in combination with other therapies could improve therapy strategies. The use of ion channels as therapeutic targets during cancer is not exclusively designed to halt cell growth. In addition, these

proteins have been also proposed as effective targets for cancer pain [56]. Furthermore, a large body of data indicates that tumour cells up-regulate KCh when undergoing dedifferentiation. This fact may also suggest that these proteins can be used as tumour markers. In conclusion, although cancer is far from being considered a channelopathy, the latest literature indicates that the time has come to consider potassium channels in anticancer therapies and to undertake organized studies.

Acknowledgements The work carried out by the Molecular Physiology Laboratory was funded by grants from the Universitat de Barcelona, the Generalitat de Catalunya and the Ministerio de Educacio´n y Ciencia (MEC), Spain awarded to AF. RV is the recipient of a fellowship from the Universitat de Barcelona. NV and RM hold fellowships from the MEC. MR-F is a research fellow of the Generalitat de Catalunya. The editorial assistance of the Language Advisory Service from the University of Barcelona is also acknowledged. The Molecular Physiology Laboratory would like to acknowledge all past members who have contributed to this research.

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