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Membrane potential and cancer progression.

Yang M, Brackenbury WJ - Front Physiol (2013)

Bottom Line: 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 Vm as a bioelectrical signal in cancer cells by examining several key types of ion channels that contribute to its regulation.The mechanisms by which Vm regulates cancer cell proliferation, migration, and differentiation will be discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of York York, UK.

ABSTRACT
Membrane potential (Vm ), the voltage across the plasma membrane, arises because of the presence of different ion channels/transporters with specific ion selectivity and permeability. Vm 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 Vm . It is well-established that cancer cells possess distinct bioelectrical properties. Notably, electrophysiological analyses in many cancer cell types have revealed a depolarized Vm that favors cell proliferation. Ion channels/transporters control cell volume and migration, and emerging data also suggest that the level of Vm 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 Vm as a bioelectrical signal in cancer cells by examining several key types of ion channels that contribute to its regulation. The mechanisms by which Vm regulates cancer cell proliferation, migration, and differentiation will be discussed. In the long term, Vm 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.

No MeSH data available.


Related in: MedlinePlus

Key ion channels that regulate Vm and cell cycle progression in cancer. Hyperpolarizing channels (outward IK, red) would increase the driving force for Ca2+ influx through voltage-independent channels, whereas inwardly rectifying K+ channels (predominantly inward IK, green) and chloride channels (outward Cl−, green) would depolarize the Vm, 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: KCa, Ca2+-activated K+ channel; EAG, ether à go-go channel; Kv, voltage-gated K+ channel; KATP, ATP-sensitive K+ channel; K2P, two-pore domain K+ channel; ERG, EAG-related gene K+ channel; Kir, classic inward-rectifier K+ channel; ClC2/3, chloride 2/3 channel.
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Figure 3: Key ion channels that regulate Vm and cell cycle progression in cancer. Hyperpolarizing channels (outward IK, red) would increase the driving force for Ca2+ influx through voltage-independent channels, whereas inwardly rectifying K+ channels (predominantly inward IK, green) and chloride channels (outward Cl−, green) would depolarize the Vm, 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: KCa, Ca2+-activated K+ channel; EAG, ether à go-go channel; Kv, voltage-gated K+ channel; KATP, ATP-sensitive K+ channel; K2P, two-pore domain K+ channel; ERG, EAG-related gene K+ channel; Kir, classic inward-rectifier K+ channel; ClC2/3, chloride 2/3 channel.

Mentions: Numerous studies have shown that pharmacological or genetic block of Kv 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 IEAG 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+ (KCa) 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).


Membrane potential and cancer progression.

Yang M, Brackenbury WJ - Front Physiol (2013)

Key ion channels that regulate Vm and cell cycle progression in cancer. Hyperpolarizing channels (outward IK, red) would increase the driving force for Ca2+ influx through voltage-independent channels, whereas inwardly rectifying K+ channels (predominantly inward IK, green) and chloride channels (outward Cl−, green) would depolarize the Vm, 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: KCa, Ca2+-activated K+ channel; EAG, ether à go-go channel; Kv, voltage-gated K+ channel; KATP, ATP-sensitive K+ channel; K2P, two-pore domain K+ channel; ERG, EAG-related gene K+ channel; Kir, classic inward-rectifier K+ channel; ClC2/3, chloride 2/3 channel.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3713347&req=5

Figure 3: Key ion channels that regulate Vm and cell cycle progression in cancer. Hyperpolarizing channels (outward IK, red) would increase the driving force for Ca2+ influx through voltage-independent channels, whereas inwardly rectifying K+ channels (predominantly inward IK, green) and chloride channels (outward Cl−, green) would depolarize the Vm, 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: KCa, Ca2+-activated K+ channel; EAG, ether à go-go channel; Kv, voltage-gated K+ channel; KATP, ATP-sensitive K+ channel; K2P, two-pore domain K+ channel; ERG, EAG-related gene K+ channel; Kir, classic inward-rectifier K+ channel; ClC2/3, chloride 2/3 channel.
Mentions: Numerous studies have shown that pharmacological or genetic block of Kv 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 IEAG 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+ (KCa) 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).

Bottom Line: 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 Vm as a bioelectrical signal in cancer cells by examining several key types of ion channels that contribute to its regulation.The mechanisms by which Vm regulates cancer cell proliferation, migration, and differentiation will be discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of York York, UK.

ABSTRACT
Membrane potential (Vm ), the voltage across the plasma membrane, arises because of the presence of different ion channels/transporters with specific ion selectivity and permeability. Vm 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 Vm . It is well-established that cancer cells possess distinct bioelectrical properties. Notably, electrophysiological analyses in many cancer cell types have revealed a depolarized Vm that favors cell proliferation. Ion channels/transporters control cell volume and migration, and emerging data also suggest that the level of Vm 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 Vm as a bioelectrical signal in cancer cells by examining several key types of ion channels that contribute to its regulation. The mechanisms by which Vm regulates cancer cell proliferation, migration, and differentiation will be discussed. In the long term, Vm 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.

No MeSH data available.


Related in: MedlinePlus