Streptomycin targets tumor-initiating cells by disrupting oxidative phosphorylation
Tumor initiating cells (TICs) are the roots of current shortcomings in advanced and metastatic cancer treatment. Endowed with self-renewal and multi-lineage differentiation capacity, TICs can disseminate and seed metastasis in distant organ. Our work identified streptomycin (SM), a potent bactericidal antibiotic, as a molecule capable of specifically targeting non-adherent TIC from colon and breast cancer cell lines. SM induces iron-dependent, reactive oxygen species (ROS)-mediated cell death, which is mechanistically distinct from RSL3-induced ferroptosis. SM-induced cell death is associated with profound alterations in mitochondrial morphology. This effect results from COX1 inhibition, which disrupts the regulation of the cytochrome c oxidase complex and triggers mitochondrial ROS production. SM's aldehyde group is essential, as its reduction into dihydrostreptomycin (DSM) abolishes its activity. These findings reveal a mechanism of action for streptomycin, shedding light on TIC metabolism and resistance, with potential implications for advanced cancer treatment.
Authors
- Benjamin Zagiel
- Amandine Bastide (ORCID: https://orcid.org/0000-0001-7896-8490)
- Chantal Cazevieille (ORCID: https://orcid.org/0000-0003-4113-1309)
- Sébastien Relier (ORCID: https://orcid.org/0000-0003-2670-9125)
- Lucile Bansard
- Béatrice Chabi (ORCID: https://orcid.org/0000-0002-5604-5668)
- Françoise Macari
- François Casas (ORCID: https://orcid.org/0000-0002-5535-8195)
- Maria Duca (ORCID: https://orcid.org/0000-0002-2666-6180)
- Hélène Guillorit (ORCID: https://orcid.org/0000-0002-4471-7260)
- Xavier Mialhe (ORCID: https://orcid.org/0000-0002-0816-7898)
- Béatrice Bonafos
- Audrey Di Giorgio
- Julie Pannequin (ORCID: https://orcid.org/0000-0002-9956-373X)
- Chris Planque
- Céline Bouclier
- Armelle Choquet (ORCID: https://orcid.org/0000-0002-6959-9387)
- Alexandre David (ORCID: https://orcid.org/0000-0003-3365-1339)
- Hélène Herault
- Szimonetta Hideg
- Bastien Felipe
- Ornella Clara
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Université Côte d'Azur (FR)
- Institut de Chimie de Nice (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Institute for Neurosciences of Montpellier (FR)
- Institut de Génomique Fonctionnelle (FR)
- Dynamique Musculaire et Métabolisme (FR)
Publication Details
- Journal
- Cell chemical biology
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1016/j.chembiol.2025.03.008
- Citations
- 3
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 2.81