KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages

A. Grimaldi, G. D'Alessandro, M. T. Golia, E. M. Grössinger, S. Di Angelantonio, D. Ragozzino, A. Santoro, V. Esposito, Heike Wulff, M. Catalano, C. Limatola

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Among the strategies adopted by glioma to successfully invade the brain parenchyma is turning the infiltrating microglia/macrophages (M/MΦ) into allies, by shifting them toward an anti-inflammatory, pro-tumor phenotype. Both glioma and infiltrating M/MΦ cells express the Ca 2+ -activated K + channel (KCa3.1), and the inhibition of KCa3.1 activity on glioma cells reduces tumor infiltration in the healthy brain parenchyma. We wondered whether KCa3.1 inhibition could prevent the acquisition of a pro-tumor phenotype by M/MΦ cells, thus contributing to reduce glioma development. With this aim, we studied microglia cultured in glioma-conditioned medium or treated with IL-4, as well as M/MΦ cells acutely isolated from glioma-bearing mice and from human glioma biopsies. Under these different conditions, M/MΦ were always polarized toward an anti-inflammatory state, and preventing KCa3.1 activation by 1-(2-Chlorophenyl)diphenylmethyl-1H-pyrazole (TRAM-34), we observed a switch toward a pro-inflammatory, antitumor phenotype. We identified FAK and PI3K/AKT as the molecular mechanisms involved in this phenotype switch, activated in sequence after KCa3.1. Anti-inflammatory M/MΦ have higher expression levels of KCa3.1 mRNA (kcnn4) that are reduced by KCa3.1 inhibition. In line with these findings, TRAM-34 treatment, in vivo, significantly reduced the size of tumors in glioma-bearing mice. Our data indicate that KCa3.1 channels are involved in the inhibitory effects exerted by the glioma microenvironment on infiltrating M/MΦ, suggesting a possible role as therapeutic targets in glioma.

Original languageEnglish (US)
Article numbere2174
JournalCell Death and Disease
Volume7
DOIs
StatePublished - Apr 7 2016

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Microglia
Glioma
Macrophages
Phenotype
Anti-Inflammatory Agents
Neoplasms
Brain
Conditioned Culture Medium
Phosphatidylinositol 3-Kinases
Interleukin-4
Biopsy
Messenger RNA

ASJC Scopus subject areas

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

Cite this

Grimaldi, A., D'Alessandro, G., Golia, M. T., Grössinger, E. M., Di Angelantonio, S., Ragozzino, D., ... Limatola, C. (2016). KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages. Cell Death and Disease, 7, [e2174]. https://doi.org/10.1038/cddis.2016.73

KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages. / Grimaldi, A.; D'Alessandro, G.; Golia, M. T.; Grössinger, E. M.; Di Angelantonio, S.; Ragozzino, D.; Santoro, A.; Esposito, V.; Wulff, Heike; Catalano, M.; Limatola, C.

In: Cell Death and Disease, Vol. 7, e2174, 07.04.2016.

Research output: Contribution to journalArticle

Grimaldi, A, D'Alessandro, G, Golia, MT, Grössinger, EM, Di Angelantonio, S, Ragozzino, D, Santoro, A, Esposito, V, Wulff, H, Catalano, M & Limatola, C 2016, 'KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages', Cell Death and Disease, vol. 7, e2174. https://doi.org/10.1038/cddis.2016.73
Grimaldi A, D'Alessandro G, Golia MT, Grössinger EM, Di Angelantonio S, Ragozzino D et al. KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages. Cell Death and Disease. 2016 Apr 7;7. e2174. https://doi.org/10.1038/cddis.2016.73
Grimaldi, A. ; D'Alessandro, G. ; Golia, M. T. ; Grössinger, E. M. ; Di Angelantonio, S. ; Ragozzino, D. ; Santoro, A. ; Esposito, V. ; Wulff, Heike ; Catalano, M. ; Limatola, C. / KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages. In: Cell Death and Disease. 2016 ; Vol. 7.
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abstract = "Among the strategies adopted by glioma to successfully invade the brain parenchyma is turning the infiltrating microglia/macrophages (M/MΦ) into allies, by shifting them toward an anti-inflammatory, pro-tumor phenotype. Both glioma and infiltrating M/MΦ cells express the Ca 2+ -activated K + channel (KCa3.1), and the inhibition of KCa3.1 activity on glioma cells reduces tumor infiltration in the healthy brain parenchyma. We wondered whether KCa3.1 inhibition could prevent the acquisition of a pro-tumor phenotype by M/MΦ cells, thus contributing to reduce glioma development. With this aim, we studied microglia cultured in glioma-conditioned medium or treated with IL-4, as well as M/MΦ cells acutely isolated from glioma-bearing mice and from human glioma biopsies. Under these different conditions, M/MΦ were always polarized toward an anti-inflammatory state, and preventing KCa3.1 activation by 1-(2-Chlorophenyl)diphenylmethyl-1H-pyrazole (TRAM-34), we observed a switch toward a pro-inflammatory, antitumor phenotype. We identified FAK and PI3K/AKT as the molecular mechanisms involved in this phenotype switch, activated in sequence after KCa3.1. Anti-inflammatory M/MΦ have higher expression levels of KCa3.1 mRNA (kcnn4) that are reduced by KCa3.1 inhibition. In line with these findings, TRAM-34 treatment, in vivo, significantly reduced the size of tumors in glioma-bearing mice. Our data indicate that KCa3.1 channels are involved in the inhibitory effects exerted by the glioma microenvironment on infiltrating M/MΦ, suggesting a possible role as therapeutic targets in glioma.",
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AU - Di Angelantonio, S.

AU - Ragozzino, D.

AU - Santoro, A.

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