Mitochondrial division inhibitor (mdivi-1) induces extracellular matrix (ECM)-detachment of viable breast cancer cells by a DRP1-independent mechanism

• Published in: Scientific reports Vol. 14; no. 1; pp. 14178 - 15
• Main Authors: Silva-Pavez, Eduardo, Mendoza, Elizabeth, Morgado-Cáceres, Pablo, Ahumada-Castro, Ulises, Bustos, Galdo, Kangme-Encalada, Matías, de Arbina, Amaia Lopez, Puebla-Huerta, Andrea, Muñoz, Felipe, Cereceda, Lucas, Varas-Godoy, Manuel, Hidalgo, Yessia, Cardenas, J. Cesar
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.06.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/45; 631/67; 631/80; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell Adhesion - drug effects; Cell detachment; Cell Line, Tumor; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Dynamins - metabolism; Electron transport chain; Extracellular matrix; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Female; Homeostasis; Humanities and Social Sciences; Humans; Mdivi-1; Metabolism; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial complex I; Mitochondrial Dynamics - drug effects; multidisciplinary; NADH-ubiquinone oxidoreductase; Pentose phosphate pathway; Quinazolinones - pharmacology; Science; Science (multidisciplinary); Mitochondrial complex I; Cell detachment; Mdivi-1; Metabolism; Cancer
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-64228-9

Increasing evidence supports the hypothesis that cancer progression is under mitochondrial control. Mitochondrial fission plays a pivotal role in the maintenance of cancer cell homeostasis. The inhibition of DRP1, the main regulator of mitochondrial fission, with the mitochondrial division inhibitor (mdivi-1) had been associated with cancer cell sensitivity to chemotherapeutics and decrease proliferation. Here, using breast cancer cells we find that mdivi-1 induces the detachment of the cells, leading to a bulk of floating cells that conserved their viability. Despite a decrease in their proliferative and clonogenic capabilities, these floating cells maintain the capacity to re-adhere upon re-seeding and retain their migratory and invasive potential. Interestingly, the cell detachment induced by mdivi-1 is independent of DRP1 but relies on inhibition of mitochondrial complex I. Furthermore, mdivi-1 induces cell detachment rely on glucose and the pentose phosphate pathway. Our data evidence a novel DRP1-independent effect of mdivi-1 in the attachment of cancer cells. The generation of floating viable cells restricts the use of mdivi-1 as a therapeutic agent and demonstrates that mdivi-1 effect on cancer cells are more complex than anticipated.