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Oncotarget. 2016 Mar 22;7(12):14259-78. doi: 10.18632/oncotarget.7423.

BK K+ channel blockade inhibits radiation-induced migration/brain infiltration of glioblastoma cells.

Author information

1
Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Tübingen, Tübingen, Germany.
2
Department of Radiation Oncology, University of Tübingen, Tübingen, Germany.
3
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, Tübingen, Germany.
4
Department of General Pediatrics, Oncology/Hematology, University of Tübingen, Tübingen, Germany.
5
Department of Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Regensburg, Germany.

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.

KEYWORDS:

fura-2 Ca2+ imaging; glioma; patch-clamp recording; radiation therapy; transfilter migration

PMID:
26893360
PMCID:
PMC4924713
DOI:
10.18632/oncotarget.7423
[Indexed for MEDLINE]
Free PMC Article

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