Targeting potassium channels in cancer

Abstract

Potassium channels are pore-forming transmembrane proteins that regulate a multitude of biological processes by controlling potassium flow across cell membranes. Aberrant potassium channel functions contribute to diseases such as epilepsy, cardiac arrhythmia, and neuromuscular symptoms collectively known as channelopathies. Increasing evidence suggests that cancer constitutes another category of channelopathies associated with dysregulated channel expression. Indeed, potassium channel-modulating agents have demonstrated antitumor efficacy. Potassium channels regulate cancer cell behaviors such as proliferation and migration through both canonical ion permeation-dependent and noncanonical ion permeation-independent functions. Given their cell surface localization and well-known pharmacology, pharmacological strategies to target potassium channel could prove to be promising cancer therapeutics.

Figure 1.

Potassium channels involved in oncogenic processes belong to all four classes. (Top) Calcium-activated potassium channels (K_Ca) and voltage-gated potassium (Kv) channels are composed of four pore-lining α subunits. Whereas SK and IK channels resemble Kv channels in having six transmembrane segments (TM1–TM6) and a reentrant pore loop between TM5 and TM6 per α subunit, BK channels have one additional transmembrane segment in the N terminus of the α subunit whereas its cytoplasmic C-terminal domain confers the channel’s calcium sensitivity. The first four transmembrane segments (TM1–TM4) of Kv channel α subunit form the voltage sensor domain, whereas the remainder of the transmembrane domain corresponds to the pore domain conserved in all potassium channels (Isacoff et al., 2013). The inward rectifying potassium channel (Kir) possesses two transmembrane domains with a pore-forming region (P) in between. The K2P channel is the so-called “background” potassium channel that is made of four transmembrane domains and two pore-forming regions. All potassium channels require a tetrameric arrangement of the pore-forming regions of the α subunits to form the potassium-selective filter, therefore a complete conductive channel is a tetramer for the one-pore channels (Kv, K_Ca, and Kir) or dimer for the K2P channels. The resting cell membrane potential is hyperpolarized due to the imbalance of potassium and sodium ion distribution caused by the electrogenic function of Na⁺-K⁺-ATPase. (Bottom) Phylogenetic dendrogram shows that the various potassium channels involved in oncogenic processes belong to all four classes.

Figure 2.

Proposed mechanisms for potassium channels to regulate cell proliferation. Potassium channels may regulate cell proliferation by four mechanisms: setting up oscillating membrane potential, controlling cell volume dynamics, regulating calcium signaling, and promoting malignant growth via noncanonical function independent of ion permeation. (1) Membrane potential oscillation has been reported in multiple proliferative cell types. A transient hyperpolarization at G1–S transition is accompanied by increased potassium channel activity. Depolarization can induce mitotic activity in several types of terminally differentiated cells. A transient depolarization at G2–M transition has been observed. Whether the potassium channel is required and the physiological significance of this depolarization at G2–M transition remain unclear. (2) Modified from Huang et al. (2012): Potassium channels can regulate cell proliferation via controlling cell volume dynamics throughout the cell cycle. This is exemplified by the voltage-gated potassium channel EAG2 that exhibits cell cycle phase–specific membrane localization. EAG2 localizes intracellularly during interphase but enriches at the plasma membrane during late G2 and mitosis. This temporal EAG2 membrane association promotes potassium efflux for premitotic condensation that is essential for mitotic entry, as well as regulating mitotic morphology for successful cell cycle progression. Temporally and spatially regulated potassium channel functions therefore may be critical for passing the “cell volume checkpoint” for successful cell cycle progression. (3) Potassium efflux through potassium channel can lead to membrane hyperpolarization, which increases the driving force for calcium entry through a calcium-permeable channel at the plasma membrane. This calcium entry can trigger calcium release from the internal store. Increased intracellular calcium concentration ([Ca²⁺]_i) can elicit calcium signaling to promote cell proliferation. (4) The potassium channel can regulate cell proliferation through a noncanonical function independent of its potassium ion permeability (indicated by the channel with red asterisks). The potassium channel can interact with membrane protein (X) or intracellular protein (Y) to initiate signaling cascade. Alternatively spliced potassium channel lacking channel domains can enter the nucleus to modulate cell function (Sun et al., 2009). How potassium channels exert noncanonical function to regulate cell proliferation remains largely unknown.

Figure 3.

Polarized ion and water flows drive local volume change and cell migration. Cell migration is characterized by the polarized cellular and molecular processes that promote the protrusion of leading edge (local volume increase) and retraction of the trailing edge (local volume reduction). A net inflow of ions and water at the cell leading edge and a net outflow of ions and water at the cell trailing edge underlie these localized hydrodynamic changes. A number of ion channels and transporters display polarized subcellular distribution during cell migration. At the trailing edge, calcium entry through calcium-permeable channels can activate calcium-activated potassium channels to promote potassium efflux. The opening of chloride channels maintains electroneutrality and further enhances the outflow of ions, which is followed by obligatory water efflux through aquaporin. At the leading edge, an assortment of inward ion channels such as voltage-gated sodium channels (Nav) or epithelial sodium channels (ENaC), or ion transporters such as sodium-proton exchangers (NHE1) or sodium-potassium-chloride cotransporters (NKCC1) together with aquaporins, regulate ion and water influx. This ion and water influx drives local cell volume increase in the protruding lamellipodium for leading edge extension. The proton extrusion and acidification of extracellular microenvironment by NHE1 can further facilitate degradation of matrix proteins and tumor cell invasion (Brisson et al., 2011). Kir4.2 localizes at the cell leading edge and enhances cell migration (deHart et al., 2008). Whether Kir4.2 conducts an inward potassium flow, which will depend on the local electrochemical gradient for potassium at the leading edge, remains unclear. For comprehensive reviews on functional roles of the ion transportome during cell migration, see Cuddapah and Sontheimer (2011), Schwab et al. (2012), and Schwab and Stock (2014).