Cancer cells are known to reprogram their metabolism to adapt to adverse conditions dictated by tumor growth and microenvironment. A subtype of cancer cells with stem-like properties, known as cancer stem cells (CSC), is thought to be responsible for tumor recurrence. In this study, we demonstrated that CSC and chemoresistant cells derived from triple negative breast cancer cells display an enrichment of up- and downregulated proteins from metabolic pathways that suggests their dependence on mitochondria for survival. Here, we selected antibiotics, in particular - linezolid, inhibiting translation of mitoribosomes and inducing mitochondrial dysfunction. We provided the first in vivo evidence demonstrating that linezolid suppressed tumor growth rate, accompanied by increased autophagy. In addition, our results revealed that bactericidal antibiotics used in combination with autophagy blocker decrease tumor growth. This study puts mitochondria in a spotlight for cancer therapy and places antibiotics as effective agents for eliminating CSC and resistant cells.

Biomedical Research in Cancer Stem Cell Group Pathology Department Vall d'Hebron Hospital 08035 Passeig Vall d'Hebron 119 129 08035 Barcelona Barcelona Spain

Biomedical Research in Cancer Stem Cell Group Pathology Department Vall d'Hebron Hospital 08035 Passeig Vall d'Hebron 119 129 08035 Barcelona Barcelona Spain;

Biomedical Research in Cancer Stem Cell Group Pathology Department Vall d'Hebron Hospital 08035 Passeig Vall d'Hebron 119 129 08035 Barcelona Barcelona Spain;; Spanish Biomedical Research Network Centre in Oncology CIBERONC Barcelona Spain

CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic;; National Centre for Biomolecular Research Faculty of Science Masaryk University Kamenice 5 62500 Brno Czech Republic

Institute for Research in Biomedicine Instituto de Salud Carlos 3 Madrid 28029 Spain

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