BK K+ Channel Blockade Inhibits Radiation-Induced migration/brain Infiltration of Glioblastoma Cells

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

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.

MeSH terms

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

Substances

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