| Autor: |
Capeloa T; Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium., Krzystyniak J; Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium., d'Hose D; Biomedical Magnetic Resonance Unit, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium., Canas Rodriguez A; Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium., Payen VL; Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium., Zampieri LX; Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium., Van de Velde JA; Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium., Benyahia Z; Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium., Pranzini E; Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.; Department of Experimental and Clinical Biomedical Sciences Mario Serio, University of Florence, Via le Morgagni 50, 50134 Firenze, Italy., Vazeille T; Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium., Fransolet M; Faculty of Sciences, Bology, Laboratoire de Biochimie et Biologie Cellulaire, University of Namur, Rue de Bruxelles 61, 5000 Namur, Belgium., Bouzin C; IREC Imaging Platform (2IP), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium., Brusa D; IREC Flow Cytometry and Cell Sorting Platform, Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium., Michiels C; Faculty of Sciences, Bology, Laboratoire de Biochimie et Biologie Cellulaire, University of Namur, Rue de Bruxelles 61, 5000 Namur, Belgium., Gallez B; Biomedical Magnetic Resonance Unit, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium., Murphy MP; MRC Mitochondrial Biology Unit, Department of Medicine, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK., Porporato PE; Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.; Department of Molecular Biotechnology and Health Science, Molecular Biotechnology Center, University of Turin, Via Nizza 52, 10126 Turin, Italy., Sonveaux P; Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. |
| Abstrakt: |
To successfully generate distant metastases, metastatic progenitor cells must simultaneously possess mesenchymal characteristics, resist to anoïkis, migrate and invade directionally, resist to redox and shear stresses in the systemic circulation, and possess stem cell characteristics. These cells primarily originate from metabolically hostile areas of the primary tumor, where oxygen and nutrient deprivation, together with metabolic waste accumulation, exert a strong selection pressure promoting evasion. Here, we followed the hypothesis according to which metastasis as a whole implies the existence of metabolic sensors. Among others, mitochondria are singled out as a major source of superoxide that supports the metastatic phenotype. Molecularly, stressed cancer cells increase mitochondrial superoxide production, which activates the transforming growth factor-β pathway through src directly within mitochondria, ultimately activating focal adhesion kinase Pyk2. The existence of mitochondria-targeted antioxidants constitutes an opportunity to interfere with the metastatic process. Here, using aggressive triple-negative and HER2-positive human breast cancer cell lines as models, we report that MitoQ inhibits all the metastatic traits that we tested in vitro. Compared to other mitochondria-targeted antioxidants, MitoQ already successfully passed Phase I safety clinical trials, which provides an important incentive for future preclinical and clinical evaluations of this drug for the prevention of breast cancer metastasis. |
