Abstract
Simple SummaryPotassium channels permit the selective passage of K+ ions across the cell me brane and are important for setting the membrane potential and for the transmission of electrical signals in all cells. Ca2+ activated K+ channels provide a means to couple intracellular calcium signaling to changes of the membrane potential. Among these, the large-conductance Ca2+-activated K+ channel, known as BK, has been proposed to be involved in several cancer-associated processes. In the present work, we tested various BK channel activators for anti-cancer effects in melanoma and pancreatic duct carcinoma cell lines. Only one of the activators (NS-11021) had effects on cancer-associated processes. However, the compound, as a side-effect, also increased the intracellular Ca2+ concentration independently of BK channel activation. Overall, we conclude that the activation of the BK channel by itself is not sufficient to produce beneficial anti-cancer effects.Potassium channels have emerged as regulators of carcinogenesis, thus introducing possible new therapeutic strategies in the fight against cancer. In particular, the large-conductance Ca2+-activated K+ channel, often referred to as BK channel, is involved in several cancer-associated processes. Here, we investigated the effects of different BK activators, NS-11021, NS-19504, and BMS-191011, in IGR39 (primary melanoma cell line) and Panc-1 (primary pancreatic duct carcinoma cell line), highly expressing the channel, and in IGR37 (metastatic melanoma cell line) that barely express BK. Our data showed that NS-11021 and NS-19504 potently activated BK channels in IGR39 and Panc-1 cells, while no effect on channel activation was detected in IGR37 cells. On the contrary, BK channel activator BMS-191011 was less effective. However, only NS-11021 showed significant effects in cancer-associated processes, such as cell survival, migration, and proliferation in these cancer cell lines. Moreover, NS-11021 led to an increase of intracellular Ca2+ concentration, independent of BK channel activation, thus complicating any interpretation of its role in the regulation of cancer-associated mechanisms. Overall, we conclude that the activation of the BK channel by itself is not sufficient to produce beneficial anti-cancer effects in the melanoma and PDAC cell lines examined. Importantly, our results raise an alarm flag regarding the use of presumably specific BK channel openers as anti-cancer agents.
Highlights
The Big Potassium (BK) voltage- and Ca2+ activated ion channel is expressed in a wide variety of cells and is commonly known by different names (Maxi-K, Slo-1, KCa1.1) [1,2].BK channels are mostly localized in the plasma membrane, they have been found in the inner mitochondrial membrane [3]
Previous studies have demonstrated that BK channels are abundantly expressed in both IGR39 [30] and Panc-1 cells [31]
In order to investigate how specific BK channel activators can influence the biological properties of these two different cancer cell lines, we studied their biophysical properties using the patch-clamp technique in the whole-cell configuration
Summary
The Big Potassium (BK) voltage- and Ca2+ activated ion channel is expressed in a wide variety of cells and is commonly known by different names (Maxi-K, Slo-1, KCa1.1) [1,2].BK channels are mostly localized in the plasma membrane, they have been found in the inner mitochondrial membrane [3]. The Big Potassium (BK) voltage- and Ca2+ activated ion channel is expressed in a wide variety of cells and is commonly known by different names (Maxi-K, Slo-1, KCa1.1) [1,2]. Each BK subunit of the homotetrameric assembly is formed by seven transmembrane segments (S0-S6), containing a voltage sensor domain (VSD, S1-S4), a pore-gate domain (PGD, S5-S6), and a cytosolic tail domain (CTD). Several associated subunits co-assemble with the main pore-forming complex in a variable manner dependent on cell type [4]. Because of the large number of protein interactions and activating factors influencing BK channel function, including intracellular Ca2+ , membrane voltage, pH, and phosphorylation [7], as well as G-proteins, steroid hormones, and various drugs [8,9], it is generally difficult to predict their effective role in different cell types [10]
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