Relevance of Abnormal KCNN1 Expression and Osmotic Hypersensitivity in Ewing Sarcoma

Ewing sarcoma (EwS) is a rare and highly malignant bone tumor occurring mainly in childhood and adolescence. Physiologically, the bone is a central hub for Ca2+ homeostasis, which is severely disturbed by osteolytic processes in EwS. Therefore, we aimed to investigate how ion transport proteins invo...

Authors: Fuest, Sebastian
Post, Christoph
Balbach, Sebastian T.
Jabar, Susanne
Neumann, Ilka
Schimmelpfennig, Sandra
Sargin, Sarah
Nass, Elke
Budde, Thomas
Kailayangiri, Sareetha
Altvater, Bianca
Ranft, Andreas
Hartmann, Wolfgang
Dirksen, Uta
Rössig, Claudia
Schwab, Albrecht
Pethö, Zoltán
Division/Institute:FB 13: Biologie
FB 05: Medizinische Fakultät
Document types:Article
Media types:Text
Publication date:2022
Date of publication on miami:16.06.2023
Modification date:16.06.2023
Edition statement:[Electronic ed.]
Source:Cancers 14 (2022) 19, 4819, 1-23
Subjects:KCa2.1 channel; Ewing sarcoma; GGAA microsatellite; regulatory volume decrease
DDC Subject:610: Medizin und Gesundheit
License:CC BY 4.0
Language:English
Funding:Finanziert durch den Open-Access-Publikationsfonds der Westfälischen Wilhelms-Universität Münster (WWU Münster).
Format:PDF document
URN:urn:nbn:de:hbz:6-30009558422
Other Identifiers:DOI: 10.17879/90019457300
Permalink:https://nbn-resolving.de/urn:nbn:de:hbz:6-30009558422
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  • Digital documents:10.3390_cancers14194819.pdf

    Ewing sarcoma (EwS) is a rare and highly malignant bone tumor occurring mainly in childhood and adolescence. Physiologically, the bone is a central hub for Ca2+ homeostasis, which is severely disturbed by osteolytic processes in EwS. Therefore, we aimed to investigate how ion transport proteins involved in Ca2+ homeostasis affect EwS pathophysiology. We characterized the expression of 22 candidate genes of Ca2+-permeable or Ca2+-regulated ion channels in three EwS cell lines and found the Ca2+-activated K+ channel KCa2.1 (KCNN1) to be exceptionally highly expressed. We revealed that 'KCNN1' expression is directly regulated by the disease-driving oncoprotein EWSR1-FL1. Due to its consistent overexpression in EwS, 'KCNN1' mRNA could be a prognostic marker in EwS. In a large cohort of EwS patients, however, 'KCNN1' mRNA quantity does not correlate with clinical parameters. Several functional studies including patch clamp electrophysiology revealed no evidence for KCa2.1 function in EwS cells. Thus, elevated KCNN1 expression is not translated to KCa2.1 channel activity in EwS cells. However, we found that the low K+ conductance of EwS cells renders them susceptible to hypoosmotic solutions. The absence of a relevant K+ conductance in EwS thereby provides an opportunity for hypoosmotic therapy that can be exploited during tumor surgery.