title: Identification of KCa3.1 Channel as a Novel Regulator of Oxidative Phosphorylation in a Subset of Pancreatic Carcinoma Cell Lines.
abstract: Pancreatic ductal adenocarcinoma (PDAC) represents the most common form of pancreatic cancer with rising incidence in developing countries and overall 5-year survival rates of less than 5%. The most frequent mutations in PDAC are gain-of-function mutations in KRAS as well as loss-of-function mutations in p53. Both mutations have severe impacts on the metabolism of tumor cells. Many of these metabolic changes are mediated by transporters or channels that regulate the exchange of metabolites and ions between the intracellular compartment and the tumor microenvironment. In the study presented here, our goal was to identify novel transporters or channels that regulate oxidative phosphorylation (OxPhos) in PDAC in order to characterize novel potential drug targets for the treatment of these cancers. We set up a Seahorse Analyzer XF based siRNA screen and identified previously described as well as novel regulators of OxPhos. The siRNA that resulted in the greatest change in cellular oxygen consumption was targeting the KCNN4 gene, which encodes for the Ca2+-sensitive K+ channel KCa3.1. This channel has not previously been reported to regulate OxPhos. Knock-down experiments as well as the use of a small molecule inhibitor confirmed its role in regulating oxygen consumption, ATP production and cellular proliferation. Furthermore, PDAC cell lines sensitive to KCa3.1 inhibition were shown to express the channel protein in the plasma membrane as well as in the mitochondria. These differences in the localization of KCa3.1 channels as well as differences in the regulation of cellular metabolism might offer opportunities for targeted therapy in subsets of PDAC.
authors: Drug Discovery, Therapeutic Research Groups / Onc II, Bayer Pharma AG, Berlin, Germany.|Department of Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.
authors: Ilya
authors: I
authors: Kovalenko
authors: Drug Discovery, Therapeutic Research Groups / Onc II, Bayer Pharma AG, Berlin, Germany.
authors: Andrea
authors: A
authors: Glasauer
authors: Drug Discovery, Therapeutic Research Groups / Onc II, Bayer Pharma AG, Berlin, Germany.
authors: Laura
authors: L
authors: Schöckel
authors: Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors: Daniel R P
authors: DR
authors: Sauter
authors: Drug Discovery, Lead Discovery / Cell Biology, Bayer Pharma AG, Berlin, Germany.
authors: Alexander
authors: A
authors: Ehrmann
authors: Drug Discovery, Therapeutic Research Groups / Bioinformatics, Bayer Pharma AG, Leverkusen, Germany.
authors: Florian
authors: F
authors: Sohler
authors: Drug Discovery, Therapeutic Research Groups / Onc II, Bayer Pharma AG, Berlin, Germany.
authors: Andrea
authors: A
authors: Hägebarth
authors: Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors: Ivana
authors: I
authors: Novak
authors: Drug Discovery, Therapeutic Research Groups / Onc II, Bayer Pharma AG, Berlin, Germany.
authors: Sven
authors: S
authors: Christian
mesh_terms: D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human