Paclitaxel Treatment and Proprotein Convertase 1/3 (PC1/3) Knockdown in Macrophages is a Promising Antiglioma Strategy as Revealed by Proteomics and Cytotoxicity Studies - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Molecular and Cellular Proteomics Année : 2018

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

Marie Duhamel
Mélanie Rose
  • Fonction : Auteur
Franck Rodet
Adriana Natalia Murgoci
  • Fonction : Auteur
Lea Zografidou
  • Fonction : Auteur
Anne Régnier-Vigouroux
  • Fonction : Auteur
Fabien Vanden Abeele
  • Fonction : Auteur
Firas Kobeissy
  • Fonction : Auteur
Maxence Wisztorski
Dasa Cizkova
  • Fonction : Auteur
Isabelle Fournier
Michel Salzet

Résumé

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 Ca2+ 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.

Dates et versions

hal-01847515 , version 1 (23-07-2018)

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Citer

Marie Duhamel, Mélanie Rose, Franck Rodet, Adriana Natalia Murgoci, Lea Zografidou, et al.. Paclitaxel Treatment and Proprotein Convertase 1/3 (PC1/3) Knockdown in Macrophages is a Promising Antiglioma Strategy as Revealed by Proteomics and Cytotoxicity Studies. Molecular and Cellular Proteomics, 2018, 17 (6), pp.1126-1143. ⟨10.1074/mcp.RA117.000443⟩. ⟨hal-01847515⟩
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