Paclitaxel Treatment and Proprotein Convertase 1/3 (PC1/3) Knockdown in Macrophages is a Promising Antiglioma Strategy as Revealed by Proteomics and Cytotoxicity Studies.

Autor:	Duhamel M; From the ‡Inserm U-1192, Laboratoire de Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM), Université Lille 1, Cité Scientifique, 59655 Villeneuve D'Ascq, France; marie.duhamel@univ-lille1.fr., Rose M; From the ‡Inserm U-1192, Laboratoire de Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM), Université Lille 1, Cité Scientifique, 59655 Villeneuve D'Ascq, France.; §Oncovet Clinical Research (OCR), SIRIC ONCOLille, Villeneuve d'Ascq, France., Rodet F; From the ‡Inserm U-1192, Laboratoire de Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM), Université Lille 1, Cité Scientifique, 59655 Villeneuve D'Ascq, France., Murgoci AN; From the ‡Inserm U-1192, Laboratoire de Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM), Université Lille 1, Cité Scientifique, 59655 Villeneuve D'Ascq, France.; §§Institute of Neuroimmunology, Slovak Academy of Sciences, 845 10, Bratislava, Slovak Republic., Zografidou L; ¶Johannes Gutenberg-Universität Mainz, Johann-Joachim-Becher-Weg 15, D-55128 Mainz, Germany., Régnier-Vigouroux A; ¶Johannes Gutenberg-Universität Mainz, Johann-Joachim-Becher-Weg 15, D-55128 Mainz, Germany., Vanden Abeele F; ‖Inserm U-1003, Equipe labellisée par la Ligue Nationale contre le cancer, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille 1, Cité Scientifique, 59655 Villeneuve d'Ascq, France., Kobeissy F; *Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut, Lebanon., Nataf S; ‡‡Inserm U-1060, CarMeN Laboratory, Banque de Tissus et de Cellules des Hospices Civils de Lyon, Université Lyon-1, Hôpital Edouard Herriot, 69437 Lyon cedex 03, France., Pays L; ‡‡Inserm U-1060, CarMeN Laboratory, Banque de Tissus et de Cellules des Hospices Civils de Lyon, Université Lyon-1, Hôpital Edouard Herriot, 69437 Lyon cedex 03, France., Wisztorski M; From the ‡Inserm U-1192, Laboratoire de Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM), Université Lille 1, Cité Scientifique, 59655 Villeneuve D'Ascq, France., Cizkova D; §§Institute of Neuroimmunology, Slovak Academy of Sciences, 845 10, Bratislava, Slovak Republic., Fournier I; From the ‡Inserm U-1192, Laboratoire de Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM), Université Lille 1, Cité Scientifique, 59655 Villeneuve D'Ascq, France., Salzet M; From the ‡Inserm U-1192, Laboratoire de Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM), Université Lille 1, Cité Scientifique, 59655 Villeneuve D'Ascq, France.
Jazyk:	angličtina
Zdroj:	Molecular & cellular proteomics : MCP [Mol Cell Proteomics] 2018 Jun; Vol. 17 (6), pp. 1126-1143. Date of Electronic Publication: 2018 Mar 12.
DOI:	10.1074/mcp.RA117.000443
Abstrakt:	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 2+ 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. (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze:	MEDLINE
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