BK K+ channel blockade inhibits radiation-induced migration/brain infiltration of glioblastoma cells
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Lena Edalat1,2,*, Benjamin Stegen2,*, Lukas Klumpp2,5, Erik Haehl2, Karin Schilbach3, Robert Lukowski1, Matthias Kühnle4, Günther Bernhardt4, Armin Buschauer4, Daniel Zips2, Peter Ruth1, Stephan M. Huber2
1Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Tübingen, Tübingen, Germany
2Department of Radiation Oncology, University of Tübingen, Tübingen, Germany
3Department of General Pediatrics, Oncology/Hematology, University of Tübingen, Tübingen, Germany
4Department of Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Regensburg, Germany
5Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, Tübingen, Germany
*These authors contributed equally to this work
Peter Ruth, e-mail: email@example.com
Stephan M. Huber, e-mail: firstname.lastname@example.org
Keywords: glioma, radiation therapy, patch-clamp recording, fura-2 Ca2+ imaging, transfilter migration
Received: October 20, 2015 Accepted: January 29, 2016 Published: February 16, 2016
Infiltration of the brain by glioblastoma cells reportedly requires Ca2+ signals and BK K+ channels that program and drive glioblastoma cell migration, respectively. Ionizing radiation (IR) has been shown to induce expression of the chemokine SDF-1, to alter the Ca2+ signaling, and to stimulate cell migration of glioblastoma cells. Here, we quantified fractionated IR-induced migration/brain infiltration of human glioblastoma cells in vitro and in an orthotopic mouse model and analyzed the role of SDF-1/CXCR4 signaling and BK channels. To this end, the radiation-induced migratory phenotypes of human T98G and far-red fluorescent U-87MG-Katushka glioblastoma cells were characterized by mRNA and protein expression, fura-2 Ca2+ imaging, BK patch-clamp recording and transfilter migration assay. In addition, U-87MG-Katushka cells were grown to solid glioblastomas in the right hemispheres of immunocompromised mice, fractionated irradiated (6 MV photons) with 5 × 0 or 5 × 2 Gy, and SDF-1, CXCR4, and BK protein expression by the tumor as well as glioblastoma brain infiltration was analyzed in dependence on BK channel targeting by systemic paxilline application concomitant to IR. As a result, IR stimulated SDF-1 signaling and induced migration of glioblastoma cells in vitro and in vivo. Importantly, paxilline blocked IR-induced migration in vivo. Collectively, our data demonstrate that fractionated IR of glioblastoma stimulates and BK K+ channel targeting mitigates migration and brain infiltration of glioblastoma cells in vivo. This suggests that BK channel targeting might represent a novel approach to overcome radiation-induced spreading of malignant brain tumors during radiotherapy.
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