mitoBK Ca is functionally expressed in murine and human breast cancer cells and promotes metabolic reprogramming-Reference-Cited by-同舟云学术

mitoBK Ca is functionally expressed in murine and human breast cancer cells and promotes metabolic reprogramming

Published:2023-12-08 Issue: Volume: Page:
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Author:

Bischof Helmut¹^ORCID,Maier Selina¹²,Koprowski Piotr³,Kulawiak Bogusz³,Burgstaller Sandra¹⁴,Jasińska Joanna³,Serafimov Kristian⁵,Gross Dominic¹,Schroth Werner²,Matt Lucas¹,Juarez Lopez David Arturo⁶,Bonzheim Irina⁷,Büttner Florian A.²,Fend Falko⁷,Schwab Matthias²⁷⁸⁹¹⁰,Birkenfeld Andreas L.⁶,Malli Roland¹¹¹²^ORCID,Lämmerhofer Michael⁵,Bednarczyk Piotr¹³,Szewczyk Adam³,Lukowski Robert¹

Affiliation:

1. Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany

2. Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstraße 112, 70376 Stuttgart, Germany

3. Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland

4. NMI Natural and Medical Sciences Institute at the University of Tuebingen, Markwiesenstraße 55, Reutlingen 72770, Germany

5. Institute of Pharmaceutical Sciences, Pharmaceutical (Bio-)Analysis, University of Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany

6. Medical Clinic IV, University Hospital Tuebingen, Otfried-Müller-Straße 10, 72076 Tuebingen, Germany

7. Institute of Pathology and Neuropathology, University Hospital Tuebingen, 72076 Tuebingen, Germany

8. Image-Guided and Functionally Instructed Tumor Therapies Cluster of Excellence (iFIT), University of Tuebingen, Roentgenweg 11, 72076 Tuebingen, Germany

9. Department of Clinical Pharmacology, University of Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany

10. Department of Biochemistry and Pharmacy, University of Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany

11. Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria

12. BioTechMed Graz, Mozartgasse 12, 8010 Graz, Austria

13. Department of Physics and Biophysics, Warsaw University of Life Sciences (SGGW), Nowoursynowska St. 159 02-776 Warsaw, Poland

Abstract

Alterations in the function of K+ channels such as the voltage- and Ca2+ activated K+ channel of large conductance (BKCa) reportedly promote breast cancer (BC) development and progression. Underlying molecular mechanisms remain, however, elusive. Here, we provide electrophysiological evidence for a BKCa splice variant localized to the inner mitochondrial membrane of murine and human BC cells (mitoBKCa). Through a combination of genetic knockdown and knockout along with cell permeable BKCa channel blocker, we show that mitoBKCa modulates overall cellular and mitochondrial energy production and mediates the metabolic rewiring referred to as the “Warburg effect”, thereby promoting BC cell proliferation in the presence and absence of oxygen. Additionally, we detect mitoBKCa and BKCa transcripts in low or high abundance, respectively, in clinical BC specimens. Together, our results emphasize, that targeting mitoBKCa, combined with established anti-cancer approaches, could represent a novel treatment strategy for selected BC patients.

Publisher

eLife Sciences Publications, Ltd