PMID- 27494181
OWN - NLM
STAT- MEDLINE
DCOM- 20170803
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 8
DP  - 2016
TI  - Identification of KCa3.1 Channel as a Novel Regulator of Oxidative 
      Phosphorylation in a Subset of Pancreatic Carcinoma Cell Lines.
PG  - e0160658
LID - 10.1371/journal.pone.0160658 [doi]
LID - e0160658
AB  - 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.
FAU - Kovalenko, Ilya
AU  - Kovalenko I
AD  - Drug Discovery, Therapeutic Research Groups / Onc II, Bayer Pharma AG, Berlin, 
      Germany.
AD  - Department of Bioanalytics, Institute of Biotechnology, Technische Universitat 
      Berlin, Berlin, Germany.
FAU - Glasauer, Andrea
AU  - Glasauer A
AD  - Drug Discovery, Therapeutic Research Groups / Onc II, Bayer Pharma AG, Berlin, 
      Germany.
FAU - Schockel, Laura
AU  - Schockel L
AD  - Drug Discovery, Therapeutic Research Groups / Onc II, Bayer Pharma AG, Berlin, 
      Germany.
FAU - Sauter, Daniel R P
AU  - Sauter DR
AD  - Section for Cell Biology and Physiology, Department of Biology, University of 
      Copenhagen, Copenhagen, Denmark.
FAU - Ehrmann, Alexander
AU  - Ehrmann A
AD  - Drug Discovery, Lead Discovery / Cell Biology, Bayer Pharma AG, Berlin, Germany.
FAU - Sohler, Florian
AU  - Sohler F
AD  - Drug Discovery, Therapeutic Research Groups / Bioinformatics, Bayer Pharma AG, 
      Leverkusen, Germany.
FAU - Hagebarth, Andrea
AU  - Hagebarth A
AD  - Drug Discovery, Therapeutic Research Groups / Onc II, Bayer Pharma AG, Berlin, 
      Germany.
FAU - Novak, Ivana
AU  - Novak I
AD  - Section for Cell Biology and Physiology, Department of Biology, University of 
      Copenhagen, Copenhagen, Denmark.
FAU - Christian, Sven
AU  - Christian S
AD  - Drug Discovery, Therapeutic Research Groups / Onc II, Bayer Pharma AG, Berlin, 
      Germany.
LA  - eng
PT  - Journal Article
DEP - 20160805
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Intermediate-Conductance Calcium-Activated Potassium Channels)
RN  - 0 (KCNN4 protein, human)
SB  - IM
MH  - Apoptosis
MH  - Carcinoma, Pancreatic Ductal/metabolism/*pathology
MH  - Cell Proliferation
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Intermediate-Conductance Calcium-Activated Potassium Channels/*metabolism
MH  - *Oxidative Phosphorylation
MH  - Pancreatic Neoplasms/metabolism/*pathology
MH  - Signal Transduction
MH  - Tumor Cells, Cultured
PMC - PMC4975431
COIS- Competing Interests: I. Kovalenko, L. Schoeckel, A. Glasauer, A. Ehrmann, F. 
      Sohler, A. Haegebarth and S. Christian are employees of Bayer Pharmaceuticals. 
      This does not alter the authors' adherence to PLOS ONE policies on sharing data 
      and materials.
EDAT- 2016/08/06 06:00
MHDA- 2017/08/05 06:00
PMCR- 2016/08/05
CRDT- 2016/08/06 06:00
PHST- 2015/12/08 00:00 [received]
PHST- 2016/07/22 00:00 [accepted]
PHST- 2016/08/06 06:00 [entrez]
PHST- 2016/08/06 06:00 [pubmed]
PHST- 2017/08/05 06:00 [medline]
PHST- 2016/08/05 00:00 [pmc-release]
AID - PONE-D-15-53260 [pii]
AID - 10.1371/journal.pone.0160658 [doi]
PST - epublish
SO  - PLoS One. 2016 Aug 5;11(8):e0160658. doi: 10.1371/journal.pone.0160658. 
      eCollection 2016.