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: Lena Edalat, Benjamin Stegen, Lukas Klumpp, Erik Haehl, Karin Schilbach, Robert Lukowski, Matthias Kühnle, Günther Bernhardt, Armin Buschauer, Daniel Zips, Peter Ruth, Stephan M Huber
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 12 Pg. 14259-78 (Mar 22 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26893360 (Publication Type: Journal Article)

Chemical References

• Biomarkers, Tumor
• CXCL12 protein, human
• CXCR4 protein, human
• Chemokine CXCL12
• Large-Conductance Calcium-Activated Potassium Channels
• Receptors, CXCR4

Topics

• Animals
• Apoptosis (radiation effects)
• Biomarkers, Tumor (metabolism)
• Brain Neoplasms (metabolism, pathology, radiotherapy)
• Cell Movement (radiation effects)
• Cell Proliferation (radiation effects)
• Chemokine CXCL12 (metabolism)
• Female
• Glioblastoma (metabolism, pathology, radiotherapy)
• Humans
• Large-Conductance Calcium-Activated Potassium Channels (antagonists & inhibitors, metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Radiation, Ionizing
• Receptors, CXCR4 (metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays