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Publications

Journal Article Epublish

PubMed: 40703453 DOI: 10.1016/j.isci.2025.113031

Mitochondrial ROS inhibition prevents doxorubicin-induced breast cancer cell migration and invasion.

iScience 28(8):113031

Authors: Tania Capeloa, Justine A Van de Velde, Erica Pranzini, Luigi Ippolito, Luca X Zampieri, Morgane Tardy, Thibaut Vazeille, Alan Provito, Giovanna Carrà, Alfonso Scalera, Valéry L Payen, Paolo E Porporato, Pierre Sonveaux

Affiliations

  • 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, 50134 Firenze, Italy.
  • Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Inserm U1019, CNRS UMR9017, Institut Pasteur de Lille, 59000 Lille, France.
  • Department of Clinical and Biological Sciences, Molecular Biotechnology Center (MBC), University of Turin, 10126 Turin, Italy.
  • San Luigi Gonzaga Hospital, 10043 Orbassano, Italy.
  • Department of Molecular Biotechnology and Health Science, Molecular Biotechnology Center (MBC), University of Turin, 10126 Turin, Italy.
  • WEL Research Institute, WELBIO Department, 1300 Wavre, Belgium.

Abstract

For cancer patients, metastasis is a life-threatening event limiting therapeutic options. Molecularly, the metastatic phenotype can be conferred by mitochondrial reactive oxygen species (mtROS) generated upon metabolic stress. Mitochondrial damage can also trigger mtROS production, which is particularly well illustrated for anthracyclines. Here, we tested in mouse models of murine and human breast cancer whether this type of chemotherapy can trigger metastasis. We report that subcytotoxic doses of doxorubicin mimicking the clinical situation in poorly perfused tumor areas sequential trigger mtROS production, activate TGFβ pathway effector Pyk2, and increase cancer cell migration and invasion. Fortunately, the metastatic switch was incompletely induced, and doxorubicin did not promote breast cancer metastasis in immunocompetent mice. Yet, MitoTEMPO fully prevented metastatic dissemination and did not interfere with doxorubicin cytotoxicity, making it attractive to combine anthracyclines with mitochondria-targeted antioxidants.

MeSH

Cells, Breast Neoplasms, Doxorubicin, Neoplasms, Mitochondria, Neoplasm Metastasis, Breast, Anthracyclines