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.

KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages / Grimaldi, Alfonso; D'Alessandro, Giuseppina; Golia, MARIA TERESA; Grössinger, E. M.; DI ANGELANTONIO, Silvia; Ragozzino, Davide Antonio; Santoro, Antonio; Esposito, Vincenzo; Wulff, H.; Catalano, Myriam; Limatola, Cristina. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 7:(2016). [10.1038/cddis.2016.73]

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

GRIMALDI, ALFONSO;D'ALESSANDRO, GIUSEPPINA;GOLIA, MARIA TERESA;DI ANGELANTONIO, SILVIA;RAGOZZINO, Davide Antonio;SANTORO, Antonio;ESPOSITO, Vincenzo;CATALANO, Myriam;LIMATOLA, Cristina
2016

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.
Cell Biology; Immunology; Cancer Research; Cellular and Molecular Neuroscience
01 Pubblicazione su rivista::01a Articolo in rivista
KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages / Grimaldi, Alfonso; D'Alessandro, Giuseppina; Golia, MARIA TERESA; Grössinger, E. M.; DI ANGELANTONIO, Silvia; Ragozzino, Davide Antonio; Santoro, Antonio; Esposito, Vincenzo; Wulff, H.; Catalano, Myriam; Limatola, Cristina. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 7:(2016). [10.1038/cddis.2016.73]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/867321
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