title: BK K+ channel blockade inhibits radiation-induced migration/brain infiltration of glioblastoma cells.
abstract: 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.
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Tübingen, Tübingen, Germany.|Department of Radiation Oncology, University of Tübingen, Tübingen, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Edalat
authors.affiliation: Department of Radiation Oncology, University of Tübingen, Tübingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Stegen
authors.affiliation: Department of Radiation Oncology, University of Tübingen, Tübingen, Germany.|Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, Tübingen, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Klumpp
authors.affiliation: Department of Radiation Oncology, University of Tübingen, Tübingen, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Haehl
authors.affiliation: Department of General Pediatrics, Oncology/Hematology, University of Tübingen, Tübingen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Schilbach
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Tübingen, Tübingen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Lukowski
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Regensburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kühnle
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Regensburg, Germany.
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Regensburg, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
authors.affiliation: Department of Radiation Oncology, University of Tübingen, Tübingen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zips
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Tübingen, Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Ruth
authors.affiliation: Department of Radiation Oncology, University of Tübingen, Tübingen, Germany.
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Huber
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D002465:Cell Movement / Q000528:radiation effects*; D049109:Cell Proliferation / Q000528:radiation effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011839:Radiation, Ionizing; D019718:Receptors, CXCR4 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D051036:Large-Conductance Calcium-Activated Potassium Channels; D019718:Receptors, CXCR4
keywords: fura-2 Ca2+ imaging; glioma; patch-clamp recording; radiation therapy; transfilter migration