KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages
| Autor: | Heike Wulff, E. M. Grössinger, Giuseppina D'Alessandro, Antonio Santoro, S. Di Angelantonio, Myriam Catalano, Vincenzo Esposito, Alfonso Grimaldi, M.T. Golia, Davide Ragozzino, Cristina Limatola |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Cancer Research Pathology medicine.medical_specialty Morpholines Immunology Biology Cell Biology Cellular and Molecular Neuroscience 03 medical and health sciences Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine Phagocytosis Glioma Cell Line Tumor Parenchyma medicine Animals Humans RNA Messenger Protein kinase B PI3K/AKT/mTOR pathway Interleukin 4 Phosphoinositide-3 Kinase Inhibitors Microglia Macrophages Brain medicine.disease Intermediate-Conductance Calcium-Activated Potassium Channels Phenotype Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Cell culture Chromones Focal Adhesion Kinase 1 Cancer research Pyrazoles Original Article Interleukin-4 Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery |
| Zdroj: | Grimaldi, A; D'Alessandro, G; Golia, MT; Grössinger, EM; Di Angelantonio, S; Ragozzino, D; et al.(2016). KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages. Cell Death and Disease, 7. doi: 10.1038/cddis.2016.73. UC Davis: Retrieved from: http://www.escholarship.org/uc/item/9sk57313 Cell Death & Disease |
| Popis: | 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 Ca2+-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. |
| Databáze: | OpenAIRE |
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