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Mol Cell Proteomics. 2015 Nov;14(11):2857-77. doi: 10.1074/mcp.M115.052480. Epub 2015 Sep 1.

Molecular Consequences of Proprotein Convertase 1/3 (PC1/3) Inhibition in Macrophages for Application to Cancer Immunotherapy: A Proteomic Study.

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From the ‡Inserm U-1192, Laboratoire de Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM), Université Lille 1, Cité Scientifique, 59655 Villeneuve D'Ascq, France;
§Institut de Biologie de Lille, UMR 8161 CNRS, Institut Pasteur de Lille, Université Lille 1, Lille, France;
¶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;
‖Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut;
**Inserm U-1060, CarMeN Laboratory, Banque de Tissus et de Cellules des Hospices Civils de Lyon, Université Lyon-1;
‡‡Institut de Pharmacologie, Département de Chirurgie/Service d'Urologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, J1H 5N4 Québec, Canada;
§§PhenoSwitch Bioscience Inc. 3001 12 Ave Nord, Sherbrooke, Qc, Canada, J1H 5N4.
From the ‡Inserm U-1192, Laboratoire de Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM), Université Lille 1, Cité Scientifique, 59655 Villeneuve D'Ascq, France;


Macrophages provide the first line of host immune defense. Their activation triggers the secretion of pro-inflammatory cytokines and chemokines recruiting other immune cells. In cancer, macrophages present an M2 anti-inflammatory phenotype promoting tumor growth. In this way, strategies need to be develop to reactivate macrophages. Previously thought to be expressed only in cells with a neural/neuroendocrine phenotype, the proprotein convertase 1/3 has been shown to also be expressed in macrophages and regulated as a function of the Toll-like receptor immune response. Here, we investigated the intracellular impact of the down-regulation of the proprotein convertase 1/3 in NR8383 macrophages and confirmed the results on macrophages from PC1/3 deficient mice. A complete proteomic study of secretomes and intracellular proteins was undertaken and revealed that inhibition of proprotein convertase 1/3 orient macrophages toward an M1 activated phenotype. This phenotype is characterized by filopodial extensions, Toll-like receptor 4 MyD88-dependent signaling, calcium entry augmentation and the secretion of pro-inflammatory factors. In response to endotoxin/lipopolysaccharide, these intracellular modifications increased, and the secreted factors attracted naïve T helper lymphocytes to promote the cytotoxic response. Importantly, the application of these factors onto breast and ovarian cancer cells resulted in a decrease viability or resistance. Under inhibitory conditions using interleukin 10, PC1/3-knockdown macrophages continued to secrete inflammatory factors. These data indicate that targeted inhibition of proprotein convertase 1/3 could represent a novel type of immune therapy to reactivate intra-tumoral macrophages.

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