Related Experiment Video
Updated: Mar 17, 2026
Oncogene Expression Analysis with Alterations in pH in a Pancreatic Ductal Cell Line
Published on: April 11, 2025
pH-sensitive K(+) channel TREK-1 is a novel target in pancreatic cancer
Daniel R P Sauter1, Christiane E Sørensen2, Markus Rapedius3
1Section 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.
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.
Insights
This study identifies TREK-1, a pH-regulated potassium channel, as a key player in pancreatic ductal adenocarcinoma (PDAC) cell behavior. Targeting TREK-1 shows potential for new PDAC therapies by inhibiting cancer cell proliferation and migration.
Area of Science:
- Oncology
- Molecular Biology
- Physiology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer requiring novel therapeutic strategies.
- Altered pH homeostasis and pH-sensing mechanisms are emerging hallmarks of cancer, influencing cell behavior.
- Two-pore domain potassium channels (K2P) are pH-sensitive ion channels involved in regulating membrane potential, with some family members implicated in tumor progression.
Purpose of the Study:
- To investigate the presence and function of pH-regulated potassium currents in PDAC cells.
- To identify the specific K2P channel responsible for pH-regulated currents in PDAC.
- To assess the role of this channel in PDAC cell proliferation and migration, and its potential as a therapeutic target.
Main Methods:
- Utilized a high-throughput patch-clamp system (SyncroPatch 384PE) to analyze ion currents in the BxPC-3 PDAC cell line.
- Employed K+ channel inhibitors and a TREK-1 specific activator (BL1249) to identify the channel component.
- Monitored plasma membrane potential (Vm) using a voltage-sensor dye (VF2.1.Cl) under varying pH conditions and with BL1249 treatment.
- Performed cell proliferation and migration assays to evaluate the functional impact of TREK-1 modulation.
Main Results:
- A significant pH-regulated potassium current was identified in BxPC-3 cells, inhibited by extracellular acidification and intracellular alkalization.
- TREK-1 (K2P2.1) was confirmed as the primary K2P channel mediating this pH-sensitive current.
- TREK-1 activity was found to be critical for setting the plasma membrane potential (Vm) in PDAC cells.
- Modulation of TREK-1 activity, particularly with the activator BL1249, significantly attenuated PDAC cell proliferation and migration, especially under acidic or alkaline conditions.
Conclusions:
- TREK-1 is a key regulator of membrane potential in PDAC cells and plays a significant role in their pathological phenotype.
- Pharmacological activation of TREK-1 inhibits PDAC cell proliferation and migration, suggesting a therapeutic benefit.
- TREK-1 represents a promising novel therapeutic target for the treatment of pancreatic ductal adenocarcinoma.
