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

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.

• Authors: 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
• Journal: Cell death & disease (Cell Death Dis) Vol. 7 Pg. e2174 (Apr 07 2016) ISSN: 2041-4889 [Electronic] England
• PMID: 27054329 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chromones
• Intermediate-Conductance Calcium-Activated Potassium Channels
• Kcnn4 protein, mouse
• Morpholines
• Phosphoinositide-3 Kinase Inhibitors
• Pyrazoles
• RNA, Messenger
• TRAM 34
• Interleukin-4
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Focal Adhesion Kinase 1
• Ptk2 protein, mouse
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Brain (metabolism, pathology)
• Cell Line, Tumor
• Chromones (pharmacology)
• Focal Adhesion Kinase 1 (genetics, metabolism)
• Glioma (drug therapy, metabolism, pathology)
• Humans
• Interleukin-4 (pharmacology)
• Intermediate-Conductance Calcium-Activated Potassium Channels (antagonists & inhibitors, genetics, metabolism)
• Macrophages (drug effects, immunology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Microglia (cytology, metabolism)
• Morpholines (pharmacology)
• Phagocytosis (drug effects)
• Phenotype
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Pyrazoles (pharmacology, therapeutic use)
• RNA, Messenger (metabolism)