KCa3.1 channels are involved in the infiltrative behavior of glioblastoma in vivo

G. D'Alessandro, M. Catalano, M. Sciaccaluga, G. Chece, R. Cipriani, M. Rosito, A. Grimaldi, C. Lauro, G. Cantore, A. Santoro, B. Fioretti, F. Franciolini, Heike Wulff, C. Limatola

Research output: Contribution to journalArticle

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Abstract

Glioblastoma multiforme (GBM) is a diffuse brain tumor characterized by high infiltration in the brain parenchyma rendering the tumor difficult to eradicate by neurosurgery. Efforts to identify molecular targets involved in the invasive behavior of GBM suggested ion channel inhibition as a promising therapeutic approach. To determine if the Ca 2+ -dependent K + channel KCa3.1 could represent a key element for GBM brain infiltration, human GL-15 cells were xenografted into the brain of SCID mice that were then treated with the specific KCa3.1 blocker TRAM-34 (1-((2-chlorophenyl) (diphenyl)methyl)-1H- pyrazole). After 5 weeks of treatment, immunofluorescence analyses of cerebral slices revealed reduced tumor infiltration and astrogliosis surrounding the tumor, compared with untreated mice. Significant reduction of tumor infiltration was also observed in the brain of mice transplanted with KCa3.1-silenced GL-15 cells, indicating a direct effect of TRAM-34 on GBM-expressed KCa3.1 channels. As KCa3.1 channels are also expressed on microglia, we investigated the effects of TRAM-34 on microglia activation in GL-15 transplanted mice and found a reduction of CD68 staining in treated mice. Similar results were observed in vitro where TRAM-34 reduced both phagocytosis and chemotactic activity of primary microglia exposed to GBM-conditioned medium. Taken together, these results indicate that KCa3.1 activity has an important role in GBM invasiveness in vivo and that its inhibition directly affects glioma cell migration and reduces astrocytosis and microglia activation in response to tumor-released factors. KCa3.1 channel inhibition therefore constitutes a potential novel therapeutic approach to reduce GBM spreading into the surrounding tissue.

Original languageEnglish (US)
Article numbere773
JournalCell Death and Disease
Volume4
Issue number8
DOIs
StatePublished - Aug 2013

Fingerprint

Glioblastoma
Microglia
Brain
Neoplasms
Gliosis
SCID Mice
Neurosurgery
Conditioned Culture Medium
Ion Channels
Phagocytosis
Brain Neoplasms
Glioma
Cell Movement
Fluorescent Antibody Technique
Therapeutics
Staining and Labeling
TRAM 34
Inhibition (Psychology)

Keywords

  • Astrocytes
  • Ca-dependent Kchannels
  • Glioblastoma
  • Invasion
  • Microglia

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

D'Alessandro, G., Catalano, M., Sciaccaluga, M., Chece, G., Cipriani, R., Rosito, M., ... Limatola, C. (2013). KCa3.1 channels are involved in the infiltrative behavior of glioblastoma in vivo. Cell Death and Disease, 4(8), [e773]. https://doi.org/10.1038/cddis.2013.279

KCa3.1 channels are involved in the infiltrative behavior of glioblastoma in vivo. / D'Alessandro, G.; Catalano, M.; Sciaccaluga, M.; Chece, G.; Cipriani, R.; Rosito, M.; Grimaldi, A.; Lauro, C.; Cantore, G.; Santoro, A.; Fioretti, B.; Franciolini, F.; Wulff, Heike; Limatola, C.

In: Cell Death and Disease, Vol. 4, No. 8, e773, 08.2013.

Research output: Contribution to journalArticle

D'Alessandro, G, Catalano, M, Sciaccaluga, M, Chece, G, Cipriani, R, Rosito, M, Grimaldi, A, Lauro, C, Cantore, G, Santoro, A, Fioretti, B, Franciolini, F, Wulff, H & Limatola, C 2013, 'KCa3.1 channels are involved in the infiltrative behavior of glioblastoma in vivo', Cell Death and Disease, vol. 4, no. 8, e773. https://doi.org/10.1038/cddis.2013.279
D'Alessandro G, Catalano M, Sciaccaluga M, Chece G, Cipriani R, Rosito M et al. KCa3.1 channels are involved in the infiltrative behavior of glioblastoma in vivo. Cell Death and Disease. 2013 Aug;4(8). e773. https://doi.org/10.1038/cddis.2013.279
D'Alessandro, G. ; Catalano, M. ; Sciaccaluga, M. ; Chece, G. ; Cipriani, R. ; Rosito, M. ; Grimaldi, A. ; Lauro, C. ; Cantore, G. ; Santoro, A. ; Fioretti, B. ; Franciolini, F. ; Wulff, Heike ; Limatola, C. / KCa3.1 channels are involved in the infiltrative behavior of glioblastoma in vivo. In: Cell Death and Disease. 2013 ; Vol. 4, No. 8.
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abstract = "Glioblastoma multiforme (GBM) is a diffuse brain tumor characterized by high infiltration in the brain parenchyma rendering the tumor difficult to eradicate by neurosurgery. Efforts to identify molecular targets involved in the invasive behavior of GBM suggested ion channel inhibition as a promising therapeutic approach. To determine if the Ca 2+ -dependent K + channel KCa3.1 could represent a key element for GBM brain infiltration, human GL-15 cells were xenografted into the brain of SCID mice that were then treated with the specific KCa3.1 blocker TRAM-34 (1-((2-chlorophenyl) (diphenyl)methyl)-1H- pyrazole). After 5 weeks of treatment, immunofluorescence analyses of cerebral slices revealed reduced tumor infiltration and astrogliosis surrounding the tumor, compared with untreated mice. Significant reduction of tumor infiltration was also observed in the brain of mice transplanted with KCa3.1-silenced GL-15 cells, indicating a direct effect of TRAM-34 on GBM-expressed KCa3.1 channels. As KCa3.1 channels are also expressed on microglia, we investigated the effects of TRAM-34 on microglia activation in GL-15 transplanted mice and found a reduction of CD68 staining in treated mice. Similar results were observed in vitro where TRAM-34 reduced both phagocytosis and chemotactic activity of primary microglia exposed to GBM-conditioned medium. Taken together, these results indicate that KCa3.1 activity has an important role in GBM invasiveness in vivo and that its inhibition directly affects glioma cell migration and reduces astrocytosis and microglia activation in response to tumor-released factors. KCa3.1 channel inhibition therefore constitutes a potential novel therapeutic approach to reduce GBM spreading into the surrounding tissue.",
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