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Paclitaxel Treatment and Proprotein Convertase 1/3 (PC1/3) Knockdown in Macrophages is a Promising Antiglioma Strategy as Revealed by Proteomics and Cytotoxicity Studies.
- Source :
-
Molecular & cellular proteomics : MCP [Mol Cell Proteomics] 2018 Jun; Vol. 17 (6), pp. 1126-1143. Date of Electronic Publication: 2018 Mar 12. - Publication Year :
- 2018
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Abstract
- High grade gliomas are the most common brain tumors in adult. These tumors are characterized by a high infiltration in microglial cells and macrophages. The immunosuppressive tumor environment is known to orient immune cells toward a pro-tumoral and anti-inflammatory phenotype. Therefore, the current challenge for cancer therapy is to find a way to reorient macrophages toward an antitumoral phenotype. Previously, we demonstrated that macrophages secreted antitumoral factors when they were invalidated for the proprotein converstase 1/3 (PC1/3) and treated with LPS. However, achieving an activation of macrophages via LPS/TLR4/Myd88-dependent pathway appears yet unfeasible in cancer patients. On the contrary, the antitumor drug Paclitaxel is also known to activate the TLR4 MyD88-dependent signaling pathway and mimics LPS action. Therefore, we evaluated if PC1/3 knock-down (KD) macrophages could be activated by Paclitaxel and efficient against glioma. We report here that such a treatment of PC1/3 KD macrophages drove to the overexpression of proteins mainly involved in cytoskeleton rearrangement. In support of this finding, we found that these cells exhibited a Ca <superscript>2+</superscript> increase after Paclitaxel treatment. This is indicative of a possible depolymerization of microtubules and may therefore reflect an activation of inflammatory pathways in macrophages. In such a way, we found that PC1/3 KD macrophages displayed a repression of the anti-inflammatory pathway STAT3 and secreted more pro-inflammatory cytokines. Extracellular vesicles isolated from these PC1/3 KD cells inhibited glioma growth. Finally, the supernatant collected from the coculture between glioma cells and PC1/3 KD macrophages contained more antitumoral factors. These findings unravel the potential value of a new therapeutic strategy combining Paclitaxel and PC1/3 inhibition to switch macrophages toward an antitumoral immunophenotype.<br /> (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Animals
Brain Neoplasms metabolism
Cell Line
Cell Survival drug effects
Coculture Techniques
Cytokines metabolism
Glioma metabolism
Macrophages drug effects
Macrophages metabolism
Proteomics
Rats
Antineoplastic Agents, Phytogenic pharmacology
Brain Neoplasms therapy
Glioma therapy
Paclitaxel pharmacology
Proprotein Convertase 1 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1535-9484
- Volume :
- 17
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Molecular & cellular proteomics : MCP
- Publication Type :
- Academic Journal
- Accession number :
- 29531019
- Full Text :
- https://doi.org/10.1074/mcp.RA117.000443