Membrane potential and cancer progression

Membrane potential (V_m), the voltage across the plasma membrane, arises because of the presence of different ion channels/transporters with specific ion selectivity and permeability. V_m is a key biophysical signal in non-excitable cells, modulating important cellular activities, such as proliferation and differentiation. Therefore, the multiplicities of various ion channels/transporters expressed on different cells are finely tuned in order to regulate the V_m. It is well-established that cancer cells possess distinct bioelectrical properties. Notably, electrophysiological analyses in many cancer cell types have revealed a depolarized V_m that favors cell proliferation. Ion channels/transporters control cell volume and migration, and emerging data also suggest that the level of V_m has functional roles in cancer cell migration. In addition, hyperpolarization is necessary for stem cell differentiation. For example, both osteogenesis and adipogenesis are hindered in human mesenchymal stem cells (hMSCs) under depolarizing conditions. Therefore, in the context of cancer, membrane depolarization might be important for the emergence and maintenance of cancer stem cells (CSCs), giving rise to sustained tumor growth. This review aims to provide a broad understanding of the V_m as a bioelectrical signal in cancer cells by examining several key types of ion channels that contribute to its regulation. The mechanisms by which V_m regulates cancer cell proliferation, migration, and differentiation will be discussed. In the long term, V_m might be a valuable clinical marker for tumor detection with prognostic value, and could even be artificially modified in order to inhibit tumor growth and metastasis.

Introduction

The presence of various ion channels and transporters at the plasma membrane provides different permeability to distinct ions, such as Na⁺, K⁺, Ca²⁺, and Cl⁻. Due to the unequal distribution of these ions, a voltage difference exists between the cytoplasm and the extracellular environment, which is known as the membrane potential (V_m). V_m is expressed relative to the extracellular environment. A cell is depolarized when the V_m is relatively less negative, whereas a hyperpolarized cell possesses a more negative V_m. V_m changes because of alterations in the conductance of one or more types of ion. The Goldman–Hodgkin–Katz equation shows that the V_m depends on the permeability (P) and both the intracellular and extracellular concentrations of major ions (Goldman, 1943; Hodgkin and Katz, 1949):

$V_m=\frac{RT}{F}\text{ln}\left(\frac{P_{{\text{Na}}^{+}}{\left[{\text{Na}}^{+}\right]}_o+P_{{\text{K}}^{+}}{\left[{\text{K}}^{+}\right]}_o+P_{{\text{Cl}}^{-}}{\left[{\text{Cl}}^{-}\right]}_o}{P_{{\text{Na}}^{+}}{\left[{\text{Na}}^{+}\right]}_i+P_{{\text{K}}^{+}}{\left[{\text{K}}^{+}\right]}_i+P_{{\text{Cl}}^{-}}{\left[{\text{Cl}}^{-}\right]}_i}\right)$

where R is the ideal gas constant, T the temperature, and F the Faraday constant. In addition, intercellular communications (e.g., gap junction connections) are also able to influence V_m (Hulser and Lauterwasser, 1982; Levin, 2007a). In excitable cells, such as neurons and muscle fibers (Nakajima and Horn, 1967; Bean, 2007), changes in V_m underlie the action potential (AP) waveform. APs fire in response to a depolarization that exceeds a threshold value. Fine-tuning of APs is tightly regulated by the activities of several key ion channels and transporters, including voltage-gated Na⁺ channels (VGSCs), voltage-gated K⁺ channels (K_v), and the Na⁺/K⁺-ATPase (Caldwell and Keynes, 1957; Hille, 1992).

Emerging evidence suggests that the V_m also plays important functional roles in non-excitable cells. In the late 1960's, while studying mitotic activities in sarcoma cells, Clarence D. Cone Jr. reported that V_m underwent hyperpolarization before entering M phase, and suggested that the level of V_m correlated with cell cycle progression (Cone, 1969). He subsequently showed that membrane hyperpolarization reversibly blocked DNA synthesis and mitosis (Cone, 1970). He later generalized existing data at that time and postulated that the V_m level was correlated with the level of differentiation. For example, terminally differentiated cells (e.g., fibroblasts and epithelium) possess hyperpolarized V_m (Cone, 1971). Since then, changes in V_m, representing the long-term, slowly changing bioelectric gradient in non-excitable cells (Lobikin et al., 2012), have been shown to control critical cell functions including proliferation, migration, and differentiation (Binggeli and Weinstein, 1986; Schwab et al., 2007; Blackiston et al., 2009; Sundelacruz et al., 2009). Recently, studies have also demonstrated that V_m is able to, directly or indirectly, control wound healing (Nuccitelli, 2003a,b; McCaig et al., 2009), left-right patterning (Adams et al., 2006), development (Nuccitelli, 2003a; Adams, 2008), and regeneration (Levin, 2007b, 2009). Therefore, given the increasing evidence showing that ion channels/transporters functionally participate in cancer progression (Kunzelmann, 2005; Fiske et al., 2006; Stuhmer et al., 2006; Prevarskaya et al., 2010; Becchetti, 2011; Brackenbury, 2012), it is not surprising that V_m has been implicated in cancer development, since V_m is itself determined by the combined activities of ion channels/transporters at the cell membrane. This article aims to summarize current understanding of the V_m as a bioelectric regulator in cancer, and examines the therapeutic potential of V_m for tumor detection and treatment.

Cancer Cells Possess Depolarized V_m

Cone's theory proposing the general correlation between proliferation and V_m (Cone, 1971) was supported by several previous studies which demonstrated significant V_m depolarization during malignant transformation of normal cells (Tokuoka and Morioka, 1957; Johnstone, 1959). Direct in vitro and in vivo comparisons of V_m levels between normal and cancerous breast cells (Marino et al., 1994), hepatocytes and hepatocellular carcinoma cells (Binggeli and Cameron, 1980; Stevenson et al., 1989), normal and neoplastic adrenocortical tissues (Lymangrover et al., 1975), normal embryonic fibroblasts and fibrosarcoma (Binggeli and Weinstein, 1985), benign and cancerous skin cells (Melczer and Kiss, 1957; Woodrough et al., 1975), and between normal and cancerous ovarian tissue (Redmann et al., 1972) showed that cancer cells tended to be more depolarized than their normal counterparts. In addition, the intracellular Na⁺ level is markedly higher in tumors compared to non-cancerous tissues, whereas the K⁺ level remains more stable (Smith et al., 1978; Cameron et al., 1980; Sparks et al., 1983). A similar scenario occurs in fast proliferating Chinese hamster ovary (CHO) and 3T3 cells (Cone and Tongier, 1973). Thus, an increased intracellular Na⁺ concentration could be a determinant of a depolarized phenotype in rapidly cycling cancer cells.

Recordings from rodent and human tissues have revealed that proliferative cells, especially rapidly proliferating tumor cells, displayed depolarized V_m, whereas non-proliferating, terminally differentiated somatic cells, such as muscle cells and neurons, are characterized by their hyperpolarized V_m (Figure 1) [reviewed in Binggeli and Weinstein (1986)]. Given these findings, is V_m merely an epiphenomenon, which only indicates the outcome of the activities of various ion channels and transporters, or is it is actually a functional instructor that is capable of promoting tumorigenesis? A similar question had been posed 50 years ago soon after Cone revealed the relationship between mitotic activity and V_m level (Cone and Tongier, 1971). For example, depolarization can initiate mitosis in CHO cells and mouse spleen lymphocytes (Cone and Tongier, 1971; Kiefer et al., 1980). By contrast, hyperpolarized V_m immediately precedes mitotic arrest (Cone and Tongier, 1973). More recently, in vivo evidence shows that membrane depolarization itself, regardless of the types of ions and ion channel/transporter proteins, is able to bring cancerous transformation (i.e., increased proliferation, change in morphology and abnormal angiogenesis) in Xenopus laevis embryos (Lobikin et al., 2012).

FIGURE 1

Figure 1. Membrane potential (V_m) scale. Rapidly proliferating cancer cells possess depolarized V_m, while the V_m of quiescent cells is generally more negative. Proliferative somatic cells are also depolarized, suggesting that V_m is functionally instructive in cell development (Levin, 2007b). Scale adapted from Binggeli and Weinstein (1986), with additional data from Fraser et al. (2005); Mycielska et al. (2005); Yang et al. (2012).

Hanahan and Weinberg proposed 10 hallmarks of cancer, including sustaining proliferative signaling, activating invasion and metastasis, and angiogenesis (Hanahan and Weinberg, 2011). The following sections review the prevailing evidence that implicates V_m in several of these processes.

V_m and Cancer Cell Proliferation

In general, in both highly proliferative tumor and non-tumor cells, depolarization is believed to serve as a signal that could initiate mitosis and DNA synthesis (Orr et al., 1972; Binggeli and Weinstein, 1986). Artificially altering V_m by modulating the extracellular ionic constitution or applying the Na⁺/K⁺-ATPase inhibitor ouabain revealed interesting results: First, hyperpolarizing CHO cells to −45 mV started to induce mitotic arrest and cell division was fully blocked at −75 mV. The cell cycle was resumed by depolarizing the cells to −10 mV (Cone, 1971). Secondly, quiescent (G₀) mature chick spinal cord neurons showed mitotic activity after depolarization (Cone and Cone, 1976) (Figure 2). Recently, artificial control of V_m was accomplished in Xenopus laevis embryos by expressing glycine-gated Cl⁻ channels and applying the activator ivermectin. Depolarization (caused by lowering the Cl⁻ concentration in the extracellular medium, which caused Cl⁻ efflux) was found to be directly responsible for malignant proliferation. This proliferation was ion and ion channel non-specific, because (1) the phenotype caused by depolarization could be rescued by expressing a hyperpolarizing channel gene, and (2) the malignant phenotype could be induced or suppressed simply by adjusting extracellular Cl⁻ concentration, as predicted by Goldman–Hodgkin–Katz equation (Lobikin et al., 2012). Therefore, the depolarized V_m frequently found in cancerous cell types could be regarded as a “sustaining proliferative signal” that instructs cells to rapidly advance in the cell cycle.

FIGURE 2

Figure 2. Membrane potential (V_m) changes during the cell cycle. V_m undergoes hyperpolarization at G₁/S border, by virtue of K⁺ efflux through various K⁺ channels. Before cells enter M phase, increased Cl⁻ efflux accompanies V_m depolarization. Quiescent cells at G₀ stage show mitotic activities after V_m depolarization (Cone and Cone, 1976).

An additional layer of complexity in this model is that the V_m fluctuates during cell cycle progression, and follows a multi-step and rhythmic pattern (Wonderlin and Strobl, 1996; Blackiston et al., 2009) (Figure 2). A number of studies suggest that membrane hyperpolarization at the G₁/S checkpoint is generally required for S phase initiation. For example, depolarizing the cell membrane halts G₁/S progression in glia (Canady et al., 1990), Schwann cells (Wilson and Chiu, 1993), lymphocytes (Price et al., 1989; Freedman et al., 1992; Wang et al., 1992), V79 Chinese hamster lung cells (Sachs et al., 1974), C1300 mouse neuroblastoma cells (Boonstra et al., 1981), and MCF-7 human breast cancer cells (Wonderlin et al., 1995). The V_m then appears to remain relatively hyperpolarized through S phase in some cell types (Sachs et al., 1974; Boonstra et al., 1981; Strobl et al., 1995; Wonderlin et al., 1995), but is more depolarized in others (Arcangeli et al., 1995; Macfarlane and Sontheimer, 2000). The G₂/M transition exhibits a depolarized V_m (Sachs et al., 1974; Boonstra et al., 1981; Blackiston et al., 2009), although it is not known whether or not this depolarization is a prerequisite for progression. In fact, the exact V_m thresholds for driving progression appear to depend heavily on cell type, the state of differentiation, and the density of cell monolayer in culture (Cone and Tongier, 1973; Blackiston et al., 2009).

Importantly, the fluctuation of V_m levels across the cell cycle does not necessarily contradict the observation that depolarized V_m could be a hallmark of cancer cells. The mean V_m values in cancer cells are consistently depolarized relative to most normal somatic cell types (Figure 1). For example, MCF-7 cells arrested at G₁ phase have a V_m of −9 mV and hyperpolarize to ~−30 mV in the S phase (Wonderlin et al., 1995). Both these values are more depolarized than normal breast cells, e.g., the mean V_m of unsynchronized MCF-10A cells is between −40 and −58 mV (Marino et al., 1994; Wonderlin et al., 1995; Fraser et al., 2005).

Evidence suggests that the fluctuation in K⁺ concentration plays a significant contribution to changes in V_m during the cell cycle. For example, in neuroblastoma and Ehrlich ascites cells, there is a transient decrease in K⁺ efflux before entering the G₂ phase, a relatively high level of K⁺ efflux during the M phase (Mills and Tupper, 1976; Boonstra et al., 1981). Given the diversity of K⁺ channel types (Hille, 1992; Miller, 2000; Wang, 2004), their relative contributions to the V_m and V_m-dependent cell cycle progression is probably context-dependent and highly complex. For example, inhibition of cell proliferation with K⁺ channel inhibitors does not correlate with changes in the V_m in rat C6 glioma cells (Rouzaire-Dubois et al., 2000). In addition, the V_m is likely to be determined by the collective activities of a variety of ions/channels/transporters, which may exhibit reciprocal interactions and form a large and complex network responsible for V_m regulation and its downstream effects.

Ion Channel-Dependent Regulation of Proliferation and V_m

Numerous studies have shown that pharmacological or genetic block of K_v channels reduces proliferation of cancer cells (e.g., Fraser et al., 2000; Ouadid-Ahidouch et al., 2000; Abdul and Hoosein, 2002; Chang et al., 2003; Menendez et al., 2010). Increasing evidence suggests that Ether à go-go (EAG) K⁺ channels may serve as biomarkers for cancer (Ouadid-Ahidouch et al., 2001; Farias et al., 2004; Pardo et al., 2005; Hemmerlein et al., 2006; Ousingsawat et al., 2007; Ortiz et al., 2011; Rodriguez-Rasgado et al., 2012). Inhibition of EAG channel expression reduces proliferation in several cancer cell lines, whereas implantation of CHO cells over-expressing EAG channels in mice induces tumors (Pardo et al., 1999). In synchronized SH-SY5Y cells, human I_EAG is reduced to less than 5% in G₁ phase, compared to unsynchronized controls, suggesting that the activity of EAG channels is cell cycle-dependent (Meyer and Heinemann, 1998). Indeed, in MCF-7 cells, inhibiting EAG channels with astemizole increases the proportion of cells in G₁ phase and reduces the proportion in S phase (Borowiec et al., 2007). In contrast, activation of hEAG channels is responsible for hyperpolarization at late G₁ before the cells enter the S phase (Ouadid-Ahidouch et al., 2001). Interestingly, the hyperpolarization is accompanied by increased Ca²⁺-activated K⁺ (K_Ca) channel currents (Ouadid-Ahidouch et al., 2001), which might result from the elevated intracellular Ca²⁺ due to the increased electrochemical gradient (Figure 3) (Nilius and Wohlrab, 1992; Ouadid-Ahidouch and Ahidouch, 2008).

FIGURE 3

Figure 3. Key ion channels that regulate V_m and cell cycle progression in cancer. Hyperpolarizing channels (outward I_K, red) would increase the driving force for Ca²⁺ influx through voltage-independent channels, whereas inwardly rectifying K⁺ channels (predominantly inward I_K, green) and chloride channels (outward Cl⁻, green) would depolarize the V_m, thus enabling activation of voltage-dependent Ca²⁺ influx (Schwab et al., 2012). Time- and domain-dependent Ca²⁺ signaling is then proposed to activate pathways that promote cell cycle progression and proliferation. Abbreviations: K_Ca, Ca²⁺-activated K⁺ channel; EAG, ether à go-go channel; K_v, voltage-gated K⁺ channel; K_ATP, ATP-sensitive K⁺ channel; K_2P, two-pore domain K⁺ channel; ERG, EAG-related gene K⁺ channel; K_ir, classic inward-rectifier K⁺ channel; ClC2/3, chloride 2/3 channel.

When K_Ca channels were found in Friend murine erythroleukemia cells, they were thought to be one of the main controllers of the V_m (Arcangeli et al., 1987). K_Ca channels have been found since in glioma (Liu et al., 2002), prostate cancer (Gessner et al., 2005), breast cancer (Haren et al., 2010), and the CD133⁺ subpopulation of SH-SY5Y cells (Park et al., 2010). Inhibiting K_Ca channels with iberiotoxin arrests D54-MG glioma cells in S phase, and leads to apoptosis (Weaver et al., 2004). Thus, the functional contribution of K_Ca channels to cell cycle regulation appears to be distinct from K_v channels. In addition, in MCF-7 cells, inhibition of ATP-sensitive K⁺ (K_ATP) channels reversibly arrests cells in the G₀/G₁ phase (Woodfork et al., 1995). The two-pore domain K⁺ channel, TREK1, increases proliferation of PC-3 and LNCaP prostate cancer cells (Voloshyna et al., 2008). In CHO cells, overexpression of TREK1 increases the number of cells in S phase, and reduces the number of cells at G₀/G₁ phase (Voloshyna et al., 2008).

Human EAG-related gene (HERG) K⁺ channels are strongly inwardly rectifying and conduct K⁺ influx when the voltage is more negative than the K⁺ equilibrium potential (Trudeau et al., 1995; Smith et al., 1996). HERG channels are expressed at early developmental stages in the neural crest, central nervous system, dorsal root ganglion (DRG) and skeletal muscle, and are replaced by classic inward rectifier K⁺ current (IK_ir) later in development (Arcangeli et al., 1997; Crociani et al., 2000). HERG channels are upregulated in a number of cancers (Arcangeli, 2005). Moreover, I_HERG increases tumor cell proliferation (Bianchi et al., 1998; Wang et al., 2002). The activity of I_HERG itself is cell cycle dependent (Arcangeli et al., 1995), suggesting a complex relationship between I_HERG, V_m, and proliferation. Additional inward rectifier K⁺ (K_ir) channels have been reported in various cancer cell types, and are required for proliferation, including K_ir2.2 (Lee et al., 2010), K_ir3.1, and K_ir3.4 (Plummer et al., 2004; Takanami et al., 2004; Plummer et al., 2005; Wagner et al., 2010). In contrast, overexpression K_ir4.1 in glioma cells hyperpolarizes the V_m and increases the number of cells in quiescent G₀/G₁, reducing the proportion in G₂/M phase (Higashimori and Sontheimer, 2007). Thus, different K_ir channels may play opposing roles in regulation of V_m/proliferation, as a result of their heterogeneous voltage dependence (Figure 3). Cl⁻ conductance also appears to be linked to the cell cycle and regulate proliferation. For example, in D54-MG cells, Cl⁻ efflux through the outward rectifying ClC3 Cl⁻ channel is significantly increased during M phase (Habela et al., 2008). In addition, the ClC2 channel is expressed in M phase in transfected NRK-49F rat kidney fibroblast cells (Zheng et al., 2002).

The mechanisms underlying ion channel-dependent proliferation of cancer cells have been reviewed in detail elsewhere (Wang, 2004; Ouadid-Ahidouch and Ahidouch, 2008; Prevarskaya et al., 2010). These include possible non-conducting, direct interactions between ion channels and other pro-proliferative signaling mechanisms. For example, coexpression of HERG and tumor necrosis factor receptor 1 (TNFR1) has been found at the cell membrane of SKBR3 and SH-SY5Y cell lines, and HERG appears to recruit TNFR1 to the membrane, therefore enhancing TNF-α-induced cancer cell proliferation (Wang et al., 2002). Alternatively, ion channel-mediated V_m hyperpolarization would increase the electrochemical gradient for Ca²⁺ and therefore elevate the intracellular Ca²⁺ concentration through voltage-independent Ca²⁺ channels, such as transient receptor potential (TRP) channels (Nilius and Wohlrab, 1992; Wang, 2004; Ouadid-Ahidouch and Ahidouch, 2008). Ca²⁺ signaling is functional across the whole cell cycle (Santella et al., 2005). For example, Ca²⁺ is required for G₁ progression and G₁/S transition (Hazelton et al., 1979; Choi et al., 2006). In turn, intracellular Ca²⁺ and calmodulin (CaM) can regulate K_Ca and EAG channels (Khanna et al., 1999; Ziechner et al., 2006; Ouadid-Ahidouch and Ahidouch, 2008). Thus, there may be a reciprocal, auto-regulatory relationship between ion channel activity, V_m, intracellular Ca²⁺ signaling, and proliferation.

In summary, a multiplicity of ion channels (predominantly K⁺-conducting) participates in V_m regulation (both depolarization and hyperpolarization) in cancer cells. In turn, changes in V_m promote transition through cell cycle checkpoints. Changes in V_m are likely to trigger intracellular signaling messengers such as Ca²⁺ in order to drive sustained proliferation.

Role of V_m in Cancer Cell Migration

Metastasis involves loss of adhesion at the primary site, increased migration and invasion, circulation through the vascular/lymphatic systems and growth of secondary tumors at distant sites (Gupta and Massague, 2006; Prevarskaya et al., 2010). Among the various steps in the metastatic cascade, it is well-established that cell migration is tightly controlled by the movement of ions and water [Figure 4; reviewed in depth in Schwab et al. (2007, 2012)]. V_m is regarded as an indirect factor that can affect cell migration, whose main regulatory role might be setting up the electrical driving force for Ca²⁺ (Prevarskaya et al., 2010; Schwab et al., 2012). A hyperpolarized V_m can increase intracellular Ca²⁺ via TRP channels, whereas membrane depolarization could activate voltage-gated Ca²⁺ channels (Schwab et al., 2012). Intracellular Ca²⁺ displays a concentration gradient in migrating cells, with lowest concentration at the leading edge (Brundage et al., 1991). During cell migration, oscillations in Ca²⁺ concentration are observed within microdomains, such that Ca²⁺ flickering is highest in the lamellipodia (Wei et al., 2009). These fluctuations play a role in regulating tractional forces (Lee et al., 1999; Ridley et al., 2003), direction sensing, and cytoskeleton reorganization (Pettit and Fay, 1998). V_m may also affect downstream intracellular signaling cascades that could contribute to cell migration in a Ca²⁺-independent way (Figure 4). For example, in kidney epithelial cells, V_m depolarization induces diphosphorylation of myosin light chain (MLC) without inducing Ca²⁺ signaling, but instead by activating the Rho-Rho kinase (ROK) pathway (Szaszi et al., 2005). In addition, actin filaments undergo reorganization following V_m depolarization in bovine eye endothelial and epithelial cells (Chifflet et al., 2003, 2004), suggesting a functional role for V_m in cytoskeletal reorganization, although it is not clear whether or not Ca²⁺ is involved. Furthermore, applied electrical fields, which would impact on V_m, can enhance motility and galvanotaxis (Djamgoz et al., 2001; Levin, 2003, 2009; Schwab et al., 2012).

FIGURE 4

Figure 4. Relationship between Na⁺, K⁺, Cl⁻ channels and V_m in cancer cell migration. V_m provides the driving force for Ca²⁺, and downstream Ca²⁺ signaling leads to cell migration (Schwab et al., 2012). V_m also regulates cytoskeleton reorganization (Chifflet et al., 2003, 2004). Cl⁻ and K⁺ channels both contribute to V_m regulation and cell volume control (Soroceanu et al., 1999; Sontheimer, 2008; Habela et al., 2009; Schwab et al., 2012). Inhibiting particular Na⁺, K⁺, and Cl⁻ channels can reduce cancer cell migration (Sontheimer, 2008; Brackenbury, 2012; Schwab et al., 2012).

A number of Na⁺, K⁺, and Cl⁻ channels, that potentially contribute to the V_m, are directly implicated in cancer cell migration. For example, functional VGSCs have been found in a number of cancer types [reviewed in Brackenbury (2012)], and suppressing VGSCs with siRNA or pharmacological agents inhibits migration and invasion (Roger et al., 2003; Fraser et al., 2005; Brackenbury et al., 2007; House et al., 2010; Yang et al., 2012). In several breast carcinoma/melanoma cell lines, K_Ca2.3, which is responsible for maintaining a hyperpolarized V_m, enhances migration, likely via promotion of intracellular Ca²⁺ signaling (Potier et al., 2006; Chantome et al., 2009). In addition, K_Ca3.1 activity causes a local shrinkage at the rear of migrating MDCK-F cells, therefore supporting retraction at this pole during movement (Schwab et al., 2006). In order to maintain electroneutrality, K⁺ efflux must be accompanied by an anion, and Cl⁻ is the most likely candidate (Schwab et al., 2007, 2012). In agreement with this, Cl⁻ channels, which contribute to the depolarized V_m in glioma cells, enhance migration and invasion by permitting the release of K⁺, Cl⁻, and water at the leading edge, resulting in shrinkage and facilitating movement into tortuous extracellular spaces (Soroceanu et al., 1999; Sontheimer, 2008; Habela et al., 2009; Schwab et al., 2012).

In conclusion, a direct role for V_m in regulating cancer cell migration is much less clear than for proliferation. Given the great variety of ion channels and transporters that are involved in the process of cell migration, the concept of the “transportome” has been proposed (Schwab et al., 2012), which implies that rather than individual ion channels or transporters, it is a complex network of ion translocators that directs the migration and invasion of cells (Figure 4). Further work is required to establish to what extent V_m directly impacts on this network.

V_m and the Differentiation of Cancer Stem Cells

Stem cells and cancer cells share similar properties, such as the ability to differentiate and self-renew, increased membrane transporter activity and the ability to migrate and metastasize (Wicha et al., 2006). The cancer stem cell (CSC) hypothesis contains two key concepts: (1) cancers arise from dysregulated transformation of normal tissue stem cells or progenitor cells, and (2) cellular components that display stem cell properties can lead to cancer progression (Wicha et al., 2006). In contrast to normal, regulated asymmetric division of stem cells during tissue homeostasis, where a stem cell produces one copy of itself and one cell that later differentiates into a mature cell, the dysregulation of transformed CSCs during tumorigenesis involves “symmetric division” in which each malign CSC generates two identical daughter cells (giving rise to either proliferation or differentiation), which significantly expands the malign stem cell reservoir (Figure 5) (Liu et al., 2005).

FIGURE 5

Figure 5. V_m in normal stem cell (SC) differentiation and hypothesized role for V_m in cancer stem cells (CSCs). Depolarized V_m is needed during the maintenance of SCs. SC undergoes asymmetric division where it produces one copy of itself and one progeny that later differentiate into mature cells. The maturation requires V_m hyperpolarization (Sundelacruz et al., 2008). However, CSCs frequently undergo symmetric division, in which one CSC divides into two identical CSC progenies (Wicha et al., 2006). Sustained V_m depolarization may help to maintain the increasing CSCs in an undifferentiated state. Proliferation of CSCs then increases cancer malignancy.

A role for V_m in differentiation of normal stem cells has been previously reported. Studies in quail neural crest cells and a subpopulation of SH-SY5Y cells have demonstrated that stem cells exhibit distinct bioelectrical profiles during development (Arcangeli et al., 1997; Biagiotti et al., 2006; Sundelacruz et al., 2009). In particular, a hyperpolarized V_m is required during stem cell maturation (Sundelacruz et al., 2009). For example, K_ir-induced V_m hyperpolarization is required during human myoblast fusion (Liu et al., 1998). In a genome-wide microarray analysis of depolarization-regulated genes in postnatal mouse cerebellar granule neurons, among 87 depolarization-responsive genes, 22 are developmentally up-regulated and 26 are developmentally down-regulated (Sato et al., 2005). Remarkably, 18 of the 22 (82%) developmentally up-regulated genes coincide with depolarization down-regulated genes, and 20 of 26 (77%) developmentally down-regulated genes with depolarization up-regulated genes (Sato et al., 2005). V_m hyperpolarization is also a functional determinant of human mesenchymal stem cell (hMSC) differentiation. Pharmacologically-induced V_m depolarization suppresses adipogenic and osteogenic differentiation of hMSCs (Sundelacruz et al., 2008). In addition, depolarization reduces the differentiated phenotype of hMSC-derived cells and improves their ability to transdifferentiate, without fully restoring a stem cell-like genetic profile (Sundelacruz et al., 2013). Taken together, these data suggest that V_m depolarization may maintain cells in an undifferentiated stage at the gene expression level. Therefore, it is not unreasonable to postulate that depolarized V_m may also help maintain a population of undifferentiated CSCs (Figure 5). This possibility would raise additional, related questions: does a more depolarized V_m promote the proliferation of CSCs? Does V_m affect the pattern of symmetric vs. asymmetric division? Further work is required to investigate these possibilities.

Clinical Implications

Given that the fluctuation of V_m can functionally regulate tumorigenesis, differentiation, and promote cancer progression, it may serve as a potential marker for tumor detection and treatment, with prognostic value. For example, bioelectrical impedance analysis, which determines tissue electrical properties, has shown promise as a prognostic indicator to monitor cancer progression (Gupta et al., 2004a,b); , and recently, the development of non-invasive, voltage-sensitive optical probes provides a potential approach for in vivo V_m measurement (Adams and Levin, 2012; Chernet and Levin, 2013). Considering the vast array of therapeutic drugs that target ion channels (Sontheimer, 2008; Stuhmer and Pardo, 2010; D'amico et al., 2013; Djamgoz and Onkal, 2013), modulating the V_m of malign tissues by adjusting the activities of varies ion channels/transporters may provide a convenient clinical approach.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This work was supported by the Medical Research Council [Fellowship number G1000508(95657)].

References

Abdul, M., and Hoosein, N. (2002). Expression and activity of potassium ion channels in human prostate cancer. Cancer Lett. 186, 99–105. doi: 10.1016/S0304-3835(02)00348-8

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Adams, D. S. (2008). A new tool for tissue engineers: ions as regulators of morphogenesis during development and regeneration. Tissue Eng. Part A 14, 1461–1468. doi: 10.1089/ten.tea.2008.0080

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Adams, D. S., and Levin, M. (2012). General principles for measuring resting membrane potential and ion concentration using fluorescent bioelectricity reporters. Cold Spring Harb. Protoc. 2012, 385–397.

Pubmed Abstract | Pubmed Full Text

Adams, D. S., Robinson, K. R., Fukumoto, T., Yuan, S., Albertson, R. C., Yelick, P., et al. (2006). Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates. Development 133, 1657–1671. doi: 10.1242/dev.02341

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Arcangeli, A. (2005). Expression and role of hERG channels in cancer cells. Novartis Found. Symp. 266, 225–232. discussion: 232–234. doi: 10.1002/047002142X.ch17

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Arcangeli, A., Bianchi, L., Becchetti, A., Faravelli, L., Coronnello, M., Mini, E., et al. (1995). A novel inward-rectifying K+ current with a cell-cycle dependence governs the resting potential of mammalian neuroblastoma cells. J. Physiol. 489(Pt 2), 455–471.

Pubmed Abstract | Pubmed Full Text

Arcangeli, A., Rosati, B., Cherubini, A., Crociani, O., Fontana, L., Ziller, C., et al. (1997). HERG- and IRK-like inward rectifier currents are sequentially expressed during neuronal development of neural crest cells and their derivatives. Eur. J. Neurosci. 9, 2596–2604. doi: 10.1111/j.1460-9568.1997.tb01689.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Arcangeli, A., Wanke, E., Olivotto, M., Camagni, S., and Ferroni, A. (1987). Three types of ion channels are present on the plasma membrane of Friend erythroleukemia cells. Biochem. Biophys. Res. Commun. 146, 1450–1457. doi: 10.1016/0006-291X(87)90812-6

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bean, B. P. (2007). The action potential in mammalian central neurons. Nat. Rev. Neurosci. 8, 451–465. doi: 10.1038/nrn2148

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Becchetti, A. (2011). Ion channels and transporters in cancer. 1. Ion channels and cell proliferation in cancer. Am. J. Physiol. Cell Physiol. 301, C255–C265. doi: 10.1152/ajpcell.00047.2011

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Biagiotti, T., D'amico, M., Marzi, I., Di Gennaro, P., Arcangeli, A., Wanke, E., et al. (2006). Cell renewing in neuroblastoma: electrophysiological and immunocytochemical characterization of stem cells and derivatives. Stem Cells 24, 443–453. doi: 10.1634/stemcells.2004-0264

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bianchi, L., Wible, B., Arcangeli, A., Taglialatela, M., Morra, F., Castaldo, P., et al. (1998). herg encodes a K+ current highly conserved in tumors of different histogenesis: a selective advantage for cancer cells? Cancer Res. 58, 815–822.

Pubmed Abstract | Pubmed Full Text

Binggeli, R., and Cameron, I. L. (1980). Cellular potentials of normal and cancerous fibroblasts and hepatocytes. Cancer Res. 40, 1830–1835.

Pubmed Abstract | Pubmed Full Text

Binggeli, R., and Weinstein, R. C. (1985). Deficits in elevating membrane potential of rat fibrosarcoma cells after cell contact. Cancer Res. 45, 235–241.

Pubmed Abstract | Pubmed Full Text

Binggeli, R., and Weinstein, R. C. (1986). Membrane potentials and sodium channels: hypotheses for growth regulation and cancer formation based on changes in sodium channels and gap junctions. J. Theor. Biol. 123, 377–401. doi: 10.1016/S0022-5193(86)80209-0

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Blackiston, D. J., McLaughlin, K. A., and Levin, M. (2009). Bioelectric controls of cell proliferation: ion channels, membrane voltage and the cell cycle. Cell Cycle 8, 3519–3528. doi: 10.4161/cc.8.21.9888

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Boonstra, J., Mummery, C. L., Tertoolen, L. G., Van Der Saag, P. T., and De Laat, S. W. (1981). Cation transport and growth regulation in neuroblastoma cells. Modulations of K+ transport and electrical membrane properties during the cell cycle. J. Cell. Physiol. 107, 75–83. doi: 10.1002/jcp.1041070110

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Borowiec, A. S., Hague, F., Harir, N., Guenin, S., Guerineau, F., Gouilleux, F., et al. (2007). IGF-1 activates hEAG K(+) channels through an Akt-dependent signaling pathway in breast cancer cells: role in cell proliferation. J. Cell. Physiol. 212, 690–701. doi: 10.1002/jcp.21065

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Brackenbury, W. J. (2012). Voltage-gated sodium channels and metastatic disease. Channels (Austin) 6, 352–361. doi: 10.4161/chan.21910

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Brackenbury, W. J., Chioni, A. M., Diss, J. K., and Djamgoz, M. B. (2007). The neonatal splice variant of Nav1.5 potentiates in vitro invasive behaviour of MDA-MB-231 human breast cancer cells. Breast Cancer Res. Treat. 101, 149–160. doi: 10.1007/s10549-006-9281-1

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Brundage, R. A., Fogarty, K. E., Tuft, R. A., and Fay, F. S. (1991). Calcium gradients underlying polarization and chemotaxis of eosinophils. Science 254, 703–706. doi: 10.1126/science.1948048

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Caldwell, P. C., and Keynes, R. D. (1957). The utilization of phosphate bond energy for sodium extrusion from giant axons. J. Physiol. 137, 12P–13P.

Pubmed Abstract | Pubmed Full Text

Cameron, I. L., Smith, N. K., Pool, T. B., and Sparks, R. L. (1980). Intracellular concentration of sodium and other elements as related to mitogenesis and oncogenesis in vivo. Cancer Res. 40, 1493–1500.

Pubmed Abstract | Pubmed Full Text

Canady, K. S., Ali-Osman, F., and Rubel, E. W. (1990). Extracellular potassium influences DNA and protein syntheses and glial fibrillary acidic protein expression in cultured glial cells. Glia 3, 368–374. doi: 10.1002/glia.440030508

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chang, K. W., Yuan, T. C., Fang, K. P., Yang, F. S., Liu, C. J., Chang, C. S., et al. (2003). The increase of voltage-gated potassium channel Kv3.4 mRNA expression in oral squamous cell carcinoma. J. Oral Pathol. Med. 32, 606–611. doi: 10.1034/j.1600-0714.2003.00197.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chantome, A., Girault, A., Potier, M., Collin, C., Vaudin, P., Pages, J. C., et al. (2009). KCa2.3 channel-dependent hyperpolarization increases melanoma cell motility. Exp. Cell Res. 315, 3620–3630. doi: 10.1016/j.yexcr.2009.07.021

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chernet, B. T., and Levin, M. (2013). Transmembrane voltage potential is an essential cellular parameter for the detection and control of tumor development in a Xenopus model. Dis. Model. Mech. 6, 595–607. doi: 10.1242/dmm.010835

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chifflet, S., Correa, V., Nin, V., Justet, C., and Hernandez, J. A. (2004). Effect of membrane potential depolarization on the organization of the actin cytoskeleton of eye epithelia. The role of adherens junctions. Exp. Eye Res. 79, 769–777. doi: 10.1016/j.exer.2004.08.031

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chifflet, S., Hernandez, J. A., Grasso, S., and Cirillo, A. (2003). Nonspecific depolarization of the plasma membrane potential induces cytoskeletal modifications of bovine corneal endothelial cells in culture. Exp. Cell Res. 282, 1–13. doi: 10.1006/excr.2002.5664

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Choi, J., Chiang, A., Taulier, N., Gros, R., Pirani, A., and Husain, M. (2006). A calmodulin-binding site on cyclin E mediates Ca2+-sensitive G1/s transitions in vascular smooth muscle cells. Circ. Res. 98, 1273–1281. doi: 10.1161/01.RES.0000223059.19250.91

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Cone, C. D. Jr. (1969). Electroosmotic interactions accompanying mitosis initation in sarcoma cells in vitro. Trans. N.Y. Acad. Sci. 31, 404–427. doi: 10.1111/j.2164-0947.1969.tb02926.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Cone, C. D. Jr. (1970). Variation of the transmembrane potential level as a basic mechanism of mitosis control. Oncology 24, 438–470. doi: 10.1159/000224545

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Cone, C. D. Jr. (1971). Unified theory on the basic mechanism of normal mitotic control and oncogenesis. J. Theor. Biol. 30, 151–181. doi: 10.1016/0022-5193(71)90042-7

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Cone, C. D. Jr., and Cone, C. M. (1976). Induction of mitosis in mature neurons in central nervous system by sustained depolarization. Science 192, 155–158. doi: 10.1126/science.56781

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Cone, C. D. Jr., and Tongier, M. Jr. (1971). Control of somatic cell mitosis by simulated changes in the transmembrane potential level. Oncology 25, 168–182. doi: 10.1159/000224567

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Cone, C. D. Jr., and Tongier, M. Jr. (1973). Contact inhibition of division: involvement of the electrical transmembrane potential. J. Cell. Physiol. 82, 373–386. doi: 10.1002/jcp.1040820307

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Crociani, O., Cherubini, A., Piccini, E., Polvani, S., Costa, L., Fontana, L., et al. (2000). erg gene(s) expression during development of the nervous and muscular system of quail embryos. Mech. Dev. 95, 239–243. doi: 10.1016/S0925-4773(00)00335-X

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

D'amico, M., Gasparoli, L., and Arcangeli, A. (2013). Potassium channels: novel emerging biomarkers and targets for therapy in cancer. Recent Pat. Anticancer Drug Discov. 8, 53–65.

Pubmed Abstract | Pubmed Full Text

Djamgoz, M. B., and Onkal, R. (2013). Persistent current blockers of voltage-gated sodium channels: a clinical opportunity for controlling metastatic disease. Recent Pat. Anticancer Drug Discov. 8, 66–84.

Pubmed Abstract | Pubmed Full Text

Djamgoz, M. B. A., Mycielska, M., Madeja, Z., Fraser, S. P., and Korohoda, W. (2001). Directional movement of rat prostate cancer cells in direct-current electric field: involvement of voltage gated Na⁺ channel activity. J. Cell Sci. 114, 2697–2705.

Pubmed Abstract | Pubmed Full Text

Farias, L. M., Ocana, D. B., Diaz, L., Larrea, F., Avila-Chavez, E., Cadena, A., et al. (2004). Ether a go-go potassium channels as human cervical cancer markers. Cancer Res. 64, 6996–7001. doi: 10.1158/0008-5472.CAN-04-1204

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Fiske, J. L., Fomin, V. P., Brown, M. L., Duncan, R. L., and Sikes, R. A. (2006). Voltage-sensitive ion channels and cancer. Cancer Metastasis Rev. 25, 493–500. doi: 10.1007/s10555-006-9017-z

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Fraser, S. P., Diss, J. K., Chioni, A. M., Mycielska, M. E., Pan, H., Yamaci, R. F., et al. (2005). Voltage-gated sodium channel expression and potentiation of human breast cancer metastasis. Clin. Cancer Res. 11, 5381–5389. doi: 10.1158/1078-0432.CCR-05-0327

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Fraser, S. P., Grimes, J. A., and Djamgoz, M. B. (2000). Effects of voltage-gated ion channel modulators on rat prostatic cancer cell proliferation: comparison of strongly and weakly metastatic cell lines. Prostate 44, 61–76.

Pubmed Abstract | Pubmed Full Text

Freedman, B. D., Price, M. A., and Deutsch, C. J. (1992). Evidence for voltage modulation of IL-2 production in mitogen-stimulated human peripheral blood lymphocytes. J. Immunol. 149, 3784–3794.

Pubmed Abstract | Pubmed Full Text

Gessner, G., Schonherr, K., Soom, M., Hansel, A., Asim, M., Baniahmad, A., et al. (2005). BKCa channels activating at resting potential without calcium in LNCaP prostate cancer cells. J. Membr. Biol. 208, 229–240. doi: 10.1007/s00232-005-0830-z

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Goldman, D. E. (1943). Potential, impedance, and rectification in membranes. J. Gen. Physiol. 27, 37–60. doi: 10.1085/jgp.27.1.37

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gupta, D., Lammersfeld, C. A., Burrows, J. L., Dahlk, S. L., Vashi, P. G., Grutsch, J. F., et al. (2004a). Bioelectrical impedance phase angle in clinical practice: implications for prognosis in advanced colorectal cancer. Am. J. Clin. Nutr. 80, 1634–1638.

Pubmed Abstract | Pubmed Full Text

Gupta, D., Lis, C. G., Dahlk, S. L., Vashi, P. G., Grutsch, J. F., and Lammersfeld, C. A. (2004b). Bioelectrical impedance phase angle as a prognostic indicator in advanced pancreatic cancer. Br. J. Nutr. 92, 957–962. doi: 10.1079/BJN20041292

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gupta, G. P., and Massague, J. (2006). Cancer metastasis: building a framework. Cell 127, 679–695. doi: 10.1016/j.cell.2006.11.001

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Habela, C. W., Ernest, N. J., Swindall, A. F., and Sontheimer, H. (2009). Chloride accumulation drives volume dynamics underlying cell proliferation and migration. J. Neurophysiol. 101, 750–757. doi: 10.1152/jn.90840.2008

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Habela, C. W., Olsen, M. L., and Sontheimer, H. (2008). ClC3 is a critical regulator of the cell cycle in normal and malignant glial cells. J. Neurosci. 28, 9205–9217. doi: 10.1523/JNEUROSCI.1897-08.2008

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hanahan, D., and Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646–674. doi: 10.1016/j.cell.2011.02.013

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Haren, N., Khorsi, H., Faouzi, M., Ahidouch, A., Sevestre, H., and Ouadid-Ahidouch, H. (2010). Intermediate conductance Ca2+ activated K+ channels are expressed and functional in breast adenocarcinomas: correlation with tumour grade and metastasis status. Histol. Histopathol. 25, 1247–1255.

Pubmed Abstract | Pubmed Full Text

Hazelton, B., Mitchell, B., and Tupper, J. (1979). Calcium, magnesium, and growth control in the WI-38 human fibroblast cell. J. Cell Biol. 83, 487–498. doi: 10.1083/jcb.83.2.487

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hemmerlein, B., Weseloh, R. M., Mello De Queiroz, F., Knotgen, H., Sanchez, A., Rubio, M. E., et al. (2006). Overexpression of Eag1 potassium channels in clinical tumours. Mol. Cancer 5:41. doi: 10.1186/1476-4598-5-41

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Higashimori, H., and Sontheimer, H. (2007). Role of Kir4.1 channels in growth control of glia. Glia 55, 1668–1679. doi: 10.1002/glia.20574

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hille, B. (1992). Ionic Channels of Excitable Membranes. Sunderland, MA: Sinauer Associates.

Hodgkin, A. L., and Katz, B. (1949). The effect of sodium ions on the electrical activity of giant axon of the squid. J. Physiol. 108, 37–77.

Pubmed Abstract | Pubmed Full Text

House, C. D., Vaske, C. J., Schwartz, A. M., Obias, V., Frank, B., Luu, T., et al. (2010). Voltage-gated Na+ channel SCN5A is a key regulator of a gene transcriptional network that controls colon cancer invasion. Cancer Res. 70, 6957–6967. doi: 10.1158/0008-5472.CAN-10-1169

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hulser, D. F., and Lauterwasser, U. (1982). Membrane potential oscillations in homokaryons. An endogenous signal for detecting intercellular communication. Exp. Cell Res. 139, 63–70. doi: 10.1016/0014-4827(82)90318-4

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Johnstone, B. M. (1959). Micro-electrode penetration of ascites tumour cells. Nature 183, 411. doi: 10.1038/183411a0

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Khanna, R., Chang, M. C., Joiner, W. J., Kaczmarek, L. K., and Schlichter, L. C. (1999). hSK4/hIK1, a calmodulin-binding KCa channel in human T lymphocytes. Roles in proliferation and volume regulation. J. Biol. Chem. 274, 14838–14849. doi: 10.1074/jbc.274.21.14838

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kiefer, H., Blume, A. J., and Kaback, H. R. (1980). Membrane potential changes during mitogenic stimulation of mouse spleen lymphocytes. Proc. Natl. Acad. Sci. U.S.A. 77, 2200–2204. doi: 10.1073/pnas.77.4.2200

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kunzelmann, K. (2005). Ion channels and cancer. J. Membr. Biol. 205, 159–173. doi: 10.1007/s00232-005-0781-4

CrossRef Full Text

Lee, I., Park, C., and Kang, W. K. (2010). Knockdown of inwardly rectifying potassium channel Kir2.2 suppresses tumorigenesis by inducing reactive oxygen species-mediated cellular senescence. Mol. Cancer Ther. 9, 2951–2959. doi: 10.1158/1535-7163.MCT-10-0511

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lee, J., Ishihara, A., Oxford, G., Johnson, B., and Jacobson, K. (1999). Regulation of cell movement is mediated by stretch-activated calcium channels. Nature 400, 382–386. doi: 10.1038/22578

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Levin, M. (2003). Bioelectromagnetics in morphogenesis. Bioelectromagnetics 24, 295–315. doi: 10.1002/bem.10104

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Levin, M. (2007a). Gap junctional communication in morphogenesis. Prog. Biophys. Mol. Biol. 94, 186–206. doi: 10.1016/j.pbiomolbio.2007.03.005

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Levin, M. (2007b). Large-scale biophysics: ion flows and regeneration. Trends Cell Biol. 17, 261–270. doi: 10.1016/j.tcb.2007.04.007

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Levin, M. (2009). Bioelectric mechanisms in regeneration: unique aspects and future perspectives. Semin. Cell Dev. Biol. 20, 543–556. doi: 10.1016/j.semcdb.2009.04.013

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Liu, J. H., Bijlenga, P., Fischer-Lougheed, J., Occhiodoro, T., Kaelin, A., Bader, C. R., et al. (1998). Role of an inward rectifier K+ current and of hyperpolarization in human myoblast fusion. J. Physiol. 510(Pt 2), 467–476. doi: 10.1111/j.1469-7793.1998.467bk.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Liu, S., Dontu, G., and Wicha, M. S. (2005). Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res. 7, 86–95. doi: 10.1186/bcr1021

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Liu, X., Chang, Y., Reinhart, P. H., Sontheimer, H., and Chang, Y. (2002). Cloning and characterization of glioma BK, a novel BK channel isoform highly expressed in human glioma cells. J. Neurosci. 22, 1840–1849.

Pubmed Abstract | Pubmed Full Text

Lobikin, M., Chernet, B., Lobo, D., and Levin, M. (2012). Resting potential, oncogene-induced tumorigenesis, and metastasis: the bioelectric basis of cancer in vivo. Phys. Biol. 9:065002. doi: 10.1088/1478-3975/9/6/065002

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lymangrover, J., Pearlmutter, A. F., Franco-Saenz, R., and Saffran, M. (1975). Transmembrane potentials and steroidogenesis in normal and neoplastic human adrenocortical tissue. J. Clin. Endocrinol. Metab. 41, 697–706. doi: 10.1210/jcem-41-4-697

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Macfarlane, S. N., and Sontheimer, H. (2000). Changes in ion channel expression accompany cell cycle progression of spinal cord astrocytes. Glia 30, 39–48.

Pubmed Abstract | Pubmed Full Text

Marino, A. A., Morris, D. M., Schwalke, M. A., Iliev, I. G., and Rogers, S. (1994). Electrical potential measurements in human breast cancer and benign lesions. Tumour Biol. 15, 147–152. doi: 10.1159/000217885

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

McCaig, C. D., Song, B., and Rajnicek, A. M. (2009). Electrical dimensions in cell science. J. Cell Sci. 122, 4267–4276. doi: 10.1242/jcs.023564

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Melczer, N., and Kiss, J. (1957). Electrical method for detection of early cancerous growth of the skin. Nature 179, 1177–1179. doi: 10.1038/1791177b0

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Menendez, S. T., Rodrigo, J. P., Allonca, E., Garcia-Carracedo, D., Alvarez-Alija, G., Casado-Zapico, S., et al. (2010). Expression and clinical significance of the Kv3.4 potassium channel subunit in the development and progression of head and neck squamous cell carcinomas. J. Pathol. 221, 402–410.

Pubmed Abstract | Pubmed Full Text

Meyer, R., and Heinemann, S. H. (1998). Characterization of an eag-like potassium channel in human neuroblastoma cells. J. Physiol. 508(Pt 1), 49–56.

Pubmed Abstract | Pubmed Full Text

Miller, C. (2000). An overview of the potassium channel family. Genome Biol. 1:REVIEWS0004. doi: 10.1186/gb-2000-1-4-reviews0004

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Mills, B., and Tupper, J. T. (1976). Cell cycle dependent changes in potassium transport. J. Cell. Physiol. 89, 123–132. doi: 10.1002/jcp.1040890112

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Mycielska, M. E., Palmer, C. P., Brackenbury, W. J., and Djamgoz, M. B. (2005). Expression of Na⁺-dependent citrate transport in a strongly metastatic human prostate cancer PC-3M cell line: regulation by voltage-gated Na⁺ channel activity. J. Physiol. 563, 393–408. doi: 10.1113/jphysiol.2004.079491

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Nakajima, A., and Horn, L. (1967). Electrical activity of single vascular smooth muscle fibers. Am. J. Physiol. 213, 25–30.

Pubmed Abstract | Pubmed Full Text

Nilius, B., and Wohlrab, W. (1992). Potassium channels and regulation of proliferation of human melanoma cells. J. Physiol. 445, 537–548.

Pubmed Abstract | Pubmed Full Text

Nuccitelli, R. (2003a). Endogenous electric fields in embryos during development, regeneration and wound healing. Radiat. Prot. Dosimetry 106, 375–383. doi: 10.1093/oxfordjournals.rpd.a006375

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Nuccitelli, R. (2003b). A role for endogenous electric fields in wound healing. Curr. Top. Dev. Biol. 58, 1–26. doi: 10.1016/S0070-2153(03)58001-2

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Orr, C. W., Yoshikawa-Fukada, M., and Ebert, J. D. (1972). Potassium: effect on DNA synthesis and multiplication of baby-hamster kidney cells: (cell cycle-membrane potential-synchronization-transformation). Proc. Natl. Acad. Sci. U.S.A. 69, 243–247. doi: 10.1073/pnas.69.1.243

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ortiz, C. S., Montante-Montes, D., Saqui-Salces, M., Hinojosa, L. M., Gamboa-Dominguez, A., Hernandez-Gallegos, E., et al. (2011). Eag1 potassium channels as markers of cervical dysplasia. Oncol. Rep. 26, 1377–1383.

Pubmed Abstract | Pubmed Full Text

Ouadid-Ahidouch, H., and Ahidouch, A. (2008). K+ channel expression in human breast cancer cells: involvement in cell cycle regulation and carcinogenesis. J. Membr. Biol. 221, 1–6. doi: 10.1007/s00232-007-9080-6

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ouadid-Ahidouch, H., Chaussade, F., Roudbaraki, M., Slomianny, C., Dewailly, E., Delcourt, P., et al. (2000). KV1.1 K(+) channels identification in human breast carcinoma cells: involvement in cell proliferation. Biochem. Biophys. Res. Commun. 278, 272–277. doi: 10.1006/bbrc.2000.3790

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ouadid-Ahidouch, H., Le Bourhis, X., Roudbaraki, M., Toillon, R. A., Delcourt, P., and Prevarskaya, N. (2001). Changes in the K+ current-density of MCF-7 cells during progression through the cell cycle: possible involvement of a h-ether.a-gogo K+ channel. Receptors Channels 7, 345–356.

Pubmed Abstract | Pubmed Full Text

Ousingsawat, J., Spitzner, M., Puntheeranurak, S., Terracciano, L., Tornillo, L., Bubendorf, L., et al. (2007). Expression of voltage-gated potassium channels in human and mouse colonic carcinoma. Clin. Cancer Res. 13, 824–831. doi: 10.1158/1078-0432.CCR-06-1940

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Pardo, L. A., Contreras-Jurado, C., Zientkowska, M., Alves, F., and Stuhmer, W. (2005). Role of voltage-gated potassium channels in cancer. J. Membr. Biol. 205, 115–124. doi: 10.1007/s00232-005-0776-1

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Pardo, L. A., Del Camino, D., Sanchez, A., Alves, F., Bruggemann, A., Beckh, S., et al. (1999). Oncogenic potential of EAG K(+) channels. EMBO J. 18, 5540–5547. doi: 10.1093/emboj/18.20.5540

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Park, J. H., Park, S. J., Chung, M. K., Jung, K. H., Choi, M. R., Kim, Y., et al. (2010). High expression of large-conductance Ca2+-activated K+ channel in the CD133+ subpopulation of SH-SY5Y neuroblastoma cells. Biochem. Biophys. Res. Commun. 396, 637–642. doi: 10.1016/j.bbrc.2010.04.142

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Pettit, E. J., and Fay, F. S. (1998). Cytosolic free calcium and the cytoskeleton in the control of leukocyte chemotaxis. Physiol. Rev. 78, 949–967.

Pubmed Abstract | Pubmed Full Text

Plummer, H. K. 3rd., Dhar, M. S., Cekanova, M., and Schuller, H. M. (2005). Expression of G-protein inwardly rectifying potassium channels (GIRKs) in lung cancer cell lines. BMC Cancer 5:104. doi: 10.1186/1471-2407-5-104

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Plummer, H. K. 3rd., Yu, Q., Cakir, Y., and Schuller, H. M. (2004). Expression of inwardly rectifying potassium channels (GIRKs) and beta-adrenergic regulation of breast cancer cell lines. BMC Cancer 4:93. doi: 10.1186/1471-2407-4-93

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Potier, M., Joulin, V., Roger, S., Besson, P., Jourdan, M. L., Leguennec, J. Y., et al. (2006). Identification of SK3 channel as a new mediator of breast cancer cell migration. Mol. Cancer Ther. 5, 2946–2953. doi: 10.1158/1535-7163.MCT-06-0194

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Prevarskaya, N., Skryma, R., and Shuba, Y. (2010). Ion channels and the hallmarks of cancer. Trends Mol. Med. 16, 107–121. doi: 10.1016/j.molmed.2010.01.005

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Price, M., Lee, S. C., and Deutsch, C. (1989). Charybdotoxin inhibits proliferation and interleukin 2 production in human peripheral blood lymphocytes. Proc. Natl. Acad. Sci. U.S.A. 86, 10171–10175. doi: 10.1073/pnas.86.24.10171

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Redmann, K., Muller, V., Tanneberger, S., and Kalkoff, W. (1972). The membrane potential of primary ovarian tumor cells in vitro and its dependence on the cell cycle. Acta Biol. Med. Ger. 28, 853–856.

Pubmed Abstract | Pubmed Full Text

Ridley, A. J., Schwartz, M. A., Burridge, K., Firtel, R. A., Ginsberg, M. H., Borisy, G., et al. (2003). Cell migration: integrating signals from front to back. Science 302, 1704–1709. doi: 10.1126/science.1092053

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Rodriguez-Rasgado, J. A., Acuna-Macias, I., and Camacho, J. (2012). Eag1 channels as potential cancer biomarkers. Sensors (Basel) 12, 5986–5995. doi: 10.3390/s120505986

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Roger, S., Besson, P., and Le Guennec, J. Y. (2003). Involvement of a novel fast inward sodium current in the invasion capacity of a breast cancer cell line. Biochim. Biophys. Acta 1616, 107–111. doi: 10.1016/j.bbamem.2003.07.001

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Rouzaire-Dubois, B., Milandri, J. B., Bostel, S., and Dubois, J. M. (2000). Control of cell proliferation by cell volume alterations in rat C6 glioma cells. Pflugers Arch. 440, 881–888. doi: 10.1007/s004240000371

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sachs, H. G., Stambrook, P. J., and Ebert, J. D. (1974). Changes in membrane potential during the cell cycle. Exp. Cell Res. 83, 362–366. doi: 10.1016/0014-4827(74)90350-4

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Santella, L., Ercolano, E., and Nusco, G. A. (2005). The cell cycle: a new entry in the field of Ca2+ signaling. Cell. Mol. Life Sci. 62, 2405–2413. doi: 10.1007/s00018-005-5083-6

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sato, M., Suzuki, K., Yamazaki, H., and Nakanishi, S. (2005). A pivotal role of calcineurin signaling in development and maturation of postnatal cerebellar granule cells. Proc. Natl. Acad. Sci. U.S.A. 102, 5874–5879. doi: 10.1073/pnas.0501972102

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Schwab, A., Fabian, A., Hanley, P. J., and Stock, C. (2012). Role of ion channels and transporters in cell migration. Physiol. Rev. 92, 1865–1913. doi: 10.1152/physrev.00018.2011

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Schwab, A., Nechyporuk-Zloy, V., Fabian, A., and Stock, C. (2007). Cells move when ions and water flow. Pflugers Arch. 453, 421–432. doi: 10.1007/s00424-006-0138-6

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Schwab, A., Wulf, A., Schulz, C., Kessler, W., Nechyporuk-Zloy, V., Romer, M., et al. (2006). Subcellular distribution of calcium-sensitive potassium channels (IK1) in migrating cells. J. Cell. Physiol. 206, 86–94. doi: 10.1002/jcp.20434

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Smith, N. R., Sparks, R. L., Pool, T. B., and Cameron, I. L. (1978). Differences in the intracellular concentration of elements in normal and cancerous liver cells as determined by X-ray microanalysis. Cancer Res. 38, 1952–1959.

Pubmed Abstract | Pubmed Full Text

Smith, P. L., Baukrowitz, T., and Yellen, G. (1996). The inward rectification mechanism of the HERG cardiac potassium channel. Nature 379, 833–836. doi: 10.1038/379833a0

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sontheimer, H. (2008). An unexpected role for ion channels in brain tumor metastasis. Exp. Biol. Med. 233, 779–791. doi: 10.3181/0711-MR-308

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Soroceanu, L., Manning, T. J. Jr., and Sontheimer, H. (1999). Modulation of glioma cell migration and invasion using Cl(-) and K(+) ion channel blockers. J. Neurosci. 19, 5942–5954.

Pubmed Abstract | Pubmed Full Text

Sparks, R. L., Pool, T. B., Smith, N. K., and Cameron, I. L. (1983). Effects of amiloride on tumor growth and intracellular element content of tumor cells in vivo. Cancer Res. 43, 73–77.

Pubmed Abstract | Pubmed Full Text

Stevenson, D., Binggeli, R., Weinstein, R. C., Keck, J. G., Lai, M. C., and Tong, M. J. (1989). Relationship between cell membrane potential and natural killer cell cytolysis in human hepatocellular carcinoma cells. Cancer Res. 49, 4842–4845.

Pubmed Abstract | Pubmed Full Text

Strobl, J. S., Wonderlin, W. F., and Flynn, D. C. (1995). Mitogenic signal transduction in human breast cancer cells. Gen. Pharmacol. 26, 1643–1649. doi: 10.1016/0306-3623(95)00062-3

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Stuhmer, W., Alves, F., Hartung, F., Zientkowska, M., and Pardo, L. A. (2006). Potassium channels as tumour markers. FEBS Lett. 580, 2850–2852. doi: 10.1016/j.febslet.2006.03.062

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Stuhmer, W., and Pardo, L. A. (2010). K(+) channels as therapeutic targets in oncology. Future Med. Chem. 2, 745–755. doi: 10.4155/fmc.10.24

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sundelacruz, S., Levin, M., and Kaplan, D. L. (2008). Membrane potential controls adipogenic and osteogenic differentiation of mesenchymal stem cells. PLoS ONE 3:e3737. doi: 10.1371/journal.pone.0003737

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sundelacruz, S., Levin, M., and Kaplan, D. L. (2009). Role of membrane potential in the regulation of cell proliferation and differentiation. Stem Cell Rev. 5, 231–246. doi: 10.1007/s12015-009-9080-2

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sundelacruz, S., Levin, M., and Kaplan, D. L. P. (2013). Depolarization alters phenotype, maintains plasticity of pre-differentiated mesenchymal stem cells. Tissue Eng. Part A doi: 10.1089/ten.tea.2012.0425.rev. [Epub ahead of print].

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Szaszi, K., Sirokmany, G., Di Ciano-Oliveira, C., Rotstein, O. D., and Kapus, A. (2005). Depolarization induces Rho-Rho kinase-mediated myosin light chain phosphorylation in kidney tubular cells. Am. J. Physiol. Cell Physiol. 289, C673–C685. doi: 10.1152/ajpcell.00481.2004

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Takanami, I., Inoue, Y., and Gika, M. (2004). G-protein inwardly rectifying potassium channel 1 (GIRK 1) gene expression correlates with tumor progression in non-small cell lung cancer. BMC Cancer 4:79. doi: 10.1186/1471-2407-4-79

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Tokuoka, S., and Morioka, H. (1957). The membrane potential of the human cancer and related cells. I. Gan 48, 353–354.

Pubmed Abstract | Pubmed Full Text

Trudeau, M. C., Warmke, J. W., Ganetzky, B., and Robertson, G. A. (1995). HERG, a human inward rectifier in the voltage-gated potassium channel family. Science 269, 92–95. doi: 10.1126/science.7604285

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Voloshyna, I., Besana, A., Castillo, M., Matos, T., Weinstein, I. B., Mansukhani, M., et al. (2008). TREK-1 is a novel molecular target in prostate cancer. Cancer Res. 68, 1197–1203. doi: 10.1158/0008-5472.CAN-07-5163

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wagner, V., Stadelmeyer, E., Riederer, M., Regitnig, P., Gorischek, A., Devaney, T., et al. (2010). Cloning and characterisation of GIRK1 variants resulting from alternative RNA editing of the KCNJ3 gene transcript in a human breast cancer cell line. J. Cell. Biochem. 110, 598–608. doi: 10.1002/jcb.22564

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wang, H., Zhang, Y., Cao, L., Han, H., Wang, J., Yang, B., et al. (2002). HERG K+ channel, a regulator of tumor cell apoptosis and proliferation. Cancer Res. 62, 4843–4848.

Pubmed Abstract | Pubmed Full Text

Wang, Y. F., Jia, H., Walker, A. M., and Cukierman, S. (1992). K-current mediation of prolactin-induced proliferation of malignant (Nb2) lymphocytes. J. Cell. Physiol. 152, 185–189. doi: 10.1002/jcp.1041520123

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wang, Z. (2004). Roles of K+ channels in regulating tumour cell proliferation and apoptosis. Pflugers Arch. 448, 274–286. doi: 10.1007/s00424-004-1258-5

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Weaver, A. K., Liu, X., and Sontheimer, H. (2004). Role for calcium-activated potassium channels (BK) in growth control of human malignant glioma cells. J. Neurosci. Res. 78, 224–234. doi: 10.1002/jnr.20240

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wei, C., Wang, X., Chen, M., Ouyang, K., Song, L. S., and Cheng, H. (2009). Calcium flickers steer cell migration. Nature 457, 901–905. doi: 10.1038/nature07577

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wicha, M. S., Liu, S., and Dontu, G. (2006). Cancer stem cells: an old idea–a paradigm shift. Cancer Res. 66, 1883–1890. discussion: 1895–1886. doi: 10.1158/0008-5472.CAN-05-3153

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wilson, G. F., and Chiu, S. Y. (1993). Mitogenic factors regulate ion channels in Schwann cells cultured from newborn rat sciatic nerve. J. Physiol. 470, 501–520.

Pubmed Abstract | Pubmed Full Text

Wonderlin, W. F., and Strobl, J. S. (1996). Potassium channels, proliferation and G1 progression. J. Membr. Biol. 154, 91–107. doi: 10.1007/s002329900135

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wonderlin, W. F., Woodfork, K. A., and Strobl, J. S. (1995). Changes in membrane potential during the progression of MCF-7 human mammary tumor cells through the cell cycle. J. Cell. Physiol. 165, 177–185. doi: 10.1002/jcp.1041650121

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Woodfork, K. A., Wonderlin, W. F., Peterson, V. A., and Strobl, J. S. (1995). Inhibition of ATP-sensitive potassium channels causes reversible cell-cycle arrest of human breast cancer cells in tissue culture. J. Cell. Physiol. 162, 163–171. doi: 10.1002/jcp.1041620202

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Woodrough, R. E., Canti, G., and Watson, B. W. (1975). Electrical potential difference between basal cell carcinoma, benign inflammatory lesions and normal tissue. Br. J. Dermatol. 92, 1–7. doi: 10.1111/j.1365-2133.1975.tb03026.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Yang, M., Kozminski, D. J., Wold, L. A., Modak, R., Calhoun, J. D., Isom, L. L., et al. (2012). Therapeutic potential for phenytoin: targeting Na(v)1.5 sodium channels to reduce migration and invasion in metastatic breast cancer. Breast Cancer Res. Treat. 134, 603–615. doi: 10.1007/s10549-012-2102-9

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Zheng, Y. J., Furukawa, T., Ogura, T., Tajimi, K., and Inagaki, N. (2002). M phase-specific expression and phosphorylation-dependent ubiquitination of the ClC-2 channel. J. Biol. Chem. 277, 32268–32273. doi: 10.1074/jbc.M202105200

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ziechner, U., Schonherr, R., Born, A. K., Gavrilova-Ruch, O., Glaser, R. W., Malesevic, M., et al. (2006). Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 273, 1074–1086. doi: 10.1111/j.1742-4658.2006.05134.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text