title: pH-sensitive K(+) channel TREK-1 is a novel target in pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and new therapeutic targets are urgently needed. One of the hallmarks of cancer is changed pH-homeostasis and potentially pH-sensors may play an important role in cancer cell behavior. Two-pore potassium channels (K2P) are pH-regulated channels that conduct a background K(+) current, which is involved in setting the plasma membrane potential (Vm). Some members of the K2P superfamily were reported as crucial players in driving tumor progression. The aim of this study was to investigate pH-regulated K(+) currents in PDAC cells and determine possible effects on their pathological phenotype. Using a planar high-throughput patch-clamp system (SyncroPatch 384PE) we identified a pH-regulated K(+) current in the PDAC cell line BxPC-3. The current was inhibited by extracellular acidification and intracellular alkalization. Exposure to a set of different K(+) channel inhibitors, and the TREK-1 (K2P2.1)-specific activator BL1249, TREK-1 was identified as the main component of pH-regulated current. A voltage-sensor dye (VF2.1.Cl) was used to monitor effects of pH and BL1249 on Vm in more physiological conditions and TREK-1-mediated current was found as critical player in setting Vm. We assessed a possible role of TREK-1 in PDAC progression using cell proliferation and migration assays and observed similar trends with attenuated proliferation/migration rates in acidic (pH<7.0) and alkaline (pH>7.4) conditions. Notably, BL1249 inhibited both PDAC cell proliferation and migration indicating that hyperpolarization of Vm attenuates cancer cell behavior. TREK-1 may therefore be a promising novel target for PDAC therapy.
authors.affiliation: Section for Cell Biology and Physiology, Department of Biology, Universitetsparken 13, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark; Nanion Technologies GmbH, Gabrielstr. 9, 80636 Munich, Germany.
authors.forename: Daniel R P
authors.initials: DR
authors.lastname: Sauter
authors.affiliation: Section for Cell Biology and Physiology, Department of Biology, Universitetsparken 13, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Christiane E
authors.initials: CE
authors.lastname: Sørensen
authors.affiliation: Nanion Technologies GmbH, Gabrielstr. 9, 80636 Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Rapedius
authors.affiliation: Nanion Technologies GmbH, Gabrielstr. 9, 80636 Munich, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brüggemann
authors.affiliation: Section for Cell Biology and Physiology, Department of Biology, Universitetsparken 13, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark. Electronic address: INovak@bio.ku.dk.
authors.forename: Ivana
authors.initials: I
authors.lastname: Novak
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1
keywords: BL1249; K(+) channel; K(2P) channel; Migration; Pancreatic adenocarcinoma; Proliferation