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, H. Wulff, M. Catalano, C. Limatola

Research output: Contribution to journalArticle

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
Article numbere2174
JournalCell Death and Disease
Volume7
DOIs
Publication statusPublished - Apr 7 2016

ASJC Scopus subject areas

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

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    Grimaldi, A., D'Alessandro, G., Golia, M. T., Grössinger, E. M., 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, 7, [e2174]. https://doi.org/10.1038/cddis.2016.73