**3. Expression profile of Kv10.1 in healthy tissues and cancer**

Kv10.1 owns very distinctive electrophysiological features that allow us to identify it in different cells. Its activation depends on the membrane potential before the stimulus [2] and when we evaluate it through a whole-cell configuration of the patch-clamp technique, we can observe how the speed of its activation increases as the membrane potential before the stimulus becomes less negative. This feature endorses Kv10.1 with the ability to "remember" the previous electrical status of the membrane and regulate its gating accordingly. This phenomenon, called Cole-Moore shift can also be analyzed in single-channel experiments, where we observe the same response, channels have a delayed opening when the pre-depolarization potential is at -120 mV contrary to the immediate opening response observed when the pre-depolarization potential is at -50 mV. When the function of Kv10.1 was being unraveled some years ago, major participation during a neuronal action potential was discarded due to its slow gating. Therefore, experiments focused on its role in the synaptic membranes. Our studies on Kv10.1 knockout (KO) mice demonstrated that the channel plays a role in postsynaptic potentiation [3]. When mice cerebellar Purkinje cells were recorded after the electrical stimulus of the granule cell layer neurons (which communicate through parallel fibers to Purkinje neurons) the cell response of KO mice was unaffected to single or low-frequency stimuli. When a train of impulses is applied, the response increases progressively with successive stimuli, but only to a certain point in the wildtype, becoming then constant even if further impulses arrive. On the other hand, when Knockout (KO) mice were recorded, the response of Purkinje cells does not become controlled and continued increasing during stimulation. This effect was only associated with mild behavioral alterations of mice under stress, and therefore, the channel seems to play roles that can be compensated by other channels under less demanding conditions.

Anyhow, during the studies on Kv10.1, we found that its expression is almost exclusively confined to the central nervous system, although our first molecular and functional studies had been made on cancer cells.

### **4. A selective advantage for cancer cells**

Therefore, we looked for the expression of Kv10.1 on a wide variety of human cell lines and cancer samples and we found that it was expressed in 72% of all tumor samples, whereas the healthy tissues where the tumor originates did not

### *Targeting the Voltage-Gated Potassium Channel Kv10.1 for Cancer Therapy DOI: http://dx.doi.org/10.5772/intechopen.99973*

express it [4]. This means that we were in front of a tailored designed cancer target, a protein absent in healthy non-central nervous system tissues but expressed in a vast majority of tumors. In addition, our studies demonstrated that tumors expressing Kv10.1 have a worse clinical behavior compared to tumors negative for the channel. Acute myeloid leukemia showed that mortality increased for Kv10.1 positive leukemias [5]. Also, other authors have reported its potential use for bad prognosis in the ovary, gastric, colon, esophagus and cervix tumors [6].

Moreover, we know that imipramine can specifically block the function of Kv10.1, and when the outcome of patients with brain metastatic tumors taking or other tricyclic antidepressants was compared to patients with similar tumors taking a non-Kv10.1 blocker as an antidepressant, we observed that survival was higher in patients with the Kv10.1 blocking treatment [7]. This result suggests that we could be able to delay tumor growth by blocking Kv10.1 and evidences the biological advantage that cells acquire when its expression begins.

If we look for the phylogeny of Kv10.1 we can identify the whole EAG family in species such as *Trichoplax adhaerens*, long before the appearance of neurons. Therefore, there must be an ancestral function of Kv10.1 that does not involve neuronal activity and excitability [8].

One of the most ancient processes of life is cell division regulation. All cells either divide at least once or descend from the division of another cell, cell division is a very universal process in cells. To divide, a cell must pass through a series of phases that have been well characterized by researchers. The S phase is characterized by the duplication of the DNA content. The M phase is Mitosis when cell division occurs. In between those phases, we find two Gap phases called G1 and G2. G1 is a growth phase when cells prepare to divide and G2 is a checkpoint after the S phase to screen for errors during DNA duplication and if absent, proceed to Mitosis. The role of membrane potential in the process was known for at least fifty years. Clarence Cone showed that the membrane potential of a cell needs to oscillate during cycles of replication [9]. If the dynamics of the membrane potential are blocked then, cell division stops. We generally accept that at the end of G1 a hyperpolarization occurs and then from the S phase to the M phase a depolarization takes place. Those changes are completely dependent on ion channels [10]. Bijlenga et al. have already demonstrated that myoblast express Kv10.1 to fusion, which is a cell cycledependent process, however insights into the details of its precise role during the cell cycle were still lacking [11]. Our group evaluated synchronized cancer cells and we could demonstrate that the expression of Kv10.1 changes during the cell cycle and is maximal during the G2 phase of cells, which can be identified by the enrichment of other G2 protein markers [12].
