The Inhibition of KCa3.1 Channels Activity Reduces Cell Motility in Glioblastoma Derived Cancer Stem Cells

Abstract

In the present study we evaluated the expression of the intermediate conductance calcium-activated potassium (KCa3.1) channel in human glioblastoma stem-like cells (CSCs) and investigated its role in cell motility. While the KCa3.1 channel is not expressed in neuronal- and glial-derived tissues of healthy individuals, both the KCa3.1 mRNA and protein are present in the glioblastoma tumor population, and are significantly enhanced in CSCs derived from both established cell line U87MG and a primary cell line, FCN9. Consistent with these data, voltage-independent and TRAM-34 sensitive potassium currents imputable to the KCa3.1 channel were recorded in the murine GL261 cell line and several primary human glioblastoma cells lines. Moreover, a significantly higher KCa3.1 current was recorded in U87MG-CD133 positive cells as compared to the U87MG-CD133 negative subpopulation. Further, we found that the tumor cell motility is strongly associated with KCa3.1 channel expression. Blockade of the KCa3.1 channel with the specific inhibitor TRAM-34 has in fact a greater impact on the motility of CSCs (reduction of 75%), which express a high level of KCa3.1 channel, than on the FCN9 parental population (reduction of 32%), where the KCa3.1 channel is expressed at lower level. Similar results were also observed with the CSCs derived from U87MG. Because invasion of surrounding tissues is one of the main causes of treatment failure in glioblastoma, these findings can be relevant for future development of novel cancer therapeutic drugs.

Ca2+-Activated IK K+ Channel Blockade Radiosensitizes Glioblastoma Cells

“…In accordance with these in vitro data is the observation that the IK inhibitor TRAM-34 blocks the brain infiltration by xenografted human glioblastoma cells in orthotopic mouse models (36). High IK channel expression has been associated with upregulation of "stemness" markers (8), and the glioblastoma "stem" cells have been suggested to express a highly migratory phenotype and to be primarily responsible for brain invasion (37,38). As a matter of fact, IK channels have been demonstrated to mediate the migration of neuronal precursor cells, so-called neuroblasts, along the rostral migratory stream to become interneurons in the olfactory bulb of normal adult mouse brain (39).…”

“…Notably, IK channels are low expressed or even absent in human astrocytes (7) but upregulated during neoplastic transformation and malignant progression of the glioma (8). This suggests a specific function of these channels in glioblastoma tumorigenesis.…”

The Inhibition by Oxaliplatin, a Platinum-Based Anti-Neoplastic Agent, of the Activity of Intermediate-Conductance Ca2+-Activated K+ Channels in Human Glioma Cells

“…Ion currents inherent in malignant glioma cells have been increasingly reported to influence the behavior of these cells [2][3][4][5][6][7][8][9][10]. Specifically, numerous reports demonstrated that any perturbations of functional expression in intermediate-conductance Ca 2+ -activated K + (IK Ca ) channels enriched in glioma cells or other types of neoplastic cells are capable of interfering with invasiveness or progression of malignant tumors [4,5,[11][12][13][14][15][16]. Alternatively, oxaliplatin (OXAL) belongs to a family of platinum-based chemotherapeutic compounds and is one of the most active drugs in many types of solid tumors encompassing gliomas [17][18][19].…”

“…The results presented herein lead us to propose that the perturbation by OXAL of IK Ca channels is another intriguing mechanism through ability of this drug and its structurally related compounds to interfere with the proliferative activity of glioma cells, if similar findings occur in vivo. The data also raise the possibility of the OXAL actions on other types of neoplastic cells in which IK Ca (or K Ca 3.1) channels are functionally expressed [5,8,[13][14][15]20].…”

A Novel Pan-Negative-Gating Modulator of KCa2/3 Channels, Fluoro-Di-Benzoate, RA-2, Inhibits Endothelium-Derived Hyperpolarization–Type Relaxation in Coronary Artery and Produces Bradycardia In Vivo

“…For extensive in-depth reviews, we refer the interested reader to Félétou et al (2010), Wulff and Castle (2010), and Wulff and Köhler (2013). Considering the patho-mechanistic roles of the channels, blockers of K Ca 3.1 channels have emerged as potential drug candidates for the treatment of sickle-cell disease (Ataga and Stocker, 2009), immunosuppression (Wulff and Castle, 2010), asthma (Van Der Velden et al, 2013), fibrosis , atherosclerosis (Toyama et al, 2008), and cancer (Ruggieri et al, 2012;D'Alessandro et al, 2013). Positive-gating modulators (activators) of K Ca 3.1, such as naphtho [1,2-d]thiazol-2-ylamine (SKA-31) (Sankaranarayanan et al, 2009) and 5-methylnaphtho [2,1-d]oxazol-2-amine (SKA-121) (Coleman et al, 2014), may improve endothelium-dependent vasodilation and lower blood pressure (Sankaranarayanan et al, 2009;Köhler et al, 2010;Damkjaer et al, 2012;Mishra et al, 2013;Radtke et al, 2013;Wulff and Köhler, 2013).…”