BK Channel in the Physiology and in the Cancer of Pancreatic Duct: Impact and Reliability of BK Openers

Abstract

BK (KCa 1.1, Slo-1) is a K+ channel characterized by an allosteric regulation of the gating mechanism by Ca2+ binding and voltage, and a high unitary conductance. The channel is expressed in many different tissues, where it is involved in the regulation or the fine-tuning of many physiological processes. Among other organs, BK is expressed in the pancreatic duct, a part of the gland important for the correct ionic composition of the pancreatic juice. Unfortunately, the pancreatic duct is also the site where one of the deadliest cancer types, the pancreatic duct adenocarcinoma (PDAC), develops. In the past years, it has been reported that continuous exposure of cancer cells to BK openers can have a significant impact on cell viability as well as on the ability to proliferate and migrate. Here, we first summarize the main BK channel properties and its roles in pancreatic duct physiology. Then we focus on the potential role of BK as a pharmacological target in PDAC. Moreover, we discuss how results obtained when employing BK activators on cancer cells can, in some cases, be misleading.

IK Channel-Independent Effects of Clotrimazole and Senicapoc on Cancer Cells Viability and Migration

“…In recent years, our lab has been studying ion channels expressed in different types of cancers [45][46][47]. In particular, we are interested in understanding the importance of these proteins in the viability, proliferation and migration of melanoma and pancreatic duct cancer cells.…”

“…We therefore applied 1 µM senicapoc (Figure 4A) or 1 µM clotrimazole (Figure 4B) to Panc-1 cells measured in the whole cell configuration with 1 µM intracellular Ca 2+ . Before drug application, large BK currents were seen in all patched cells [45,52], and none of the drugs had an appreciable effect (Figure 4A-C). Conversely, the subsequent application of 1 µM paxilline blocked most of the currents as expected (Figure 4A-C).…”

Challenges in the Therapeutic Targeting of KCa Channels: From Basic Physiology to Clinical Applications

“…The activation of BK channels can lead to bronchodilation, facilitating airflow in the lungs [ 69 ]. Furthermore, BK channels are associated with various potential physiological functions, including cell metastasis and the activation/migration of non-excitable cells such as fibroblasts [ 70 ].…”

Functional expression of the proton sensors ASIC1a, TMEM206, and OGR1 together with BKCa channels is associated with cell volume changes and cell death under strongly acidic conditions in DAOY medulloblastoma cells

“…In DAOY cells, OGR1 activation increases intracellular Ca 2+ concentration [Ca 2+ ] i and activates the MEK/ERK pathway under mild acidic conditions [16]. BK Ca channels have been studied quite extensively in gliomas and other tumors where they are often associated with tumor proliferation and migration [19][20][21][22]. BK Ca and other K + channels have been associated with cell volume regulation, especially regarding cell cycle progression [23][24][25].…”