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Common Metabolic Pathways Implicated in Resistance to Chemotherapy Point to a Key Mitochondrial Role in Breast Cancer

E. Abad, Y. García-Mayea, C. Mir, D. Sebastian, A. Zorzano, D. Potesil, Z. Zdrahal, A. Lyakhovich, ME. Lleonart,

. 2019 ; 18 (2) : 231-244. [pub] 20181029

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc19045166

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.

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$a Cancer cells are known to reprogram their metabolism to adapt to adverse conditions dictated by tumor growth and microenvironment. A subtype of cancer cells with stem-like properties, known as cancer stem cells (CSC), is thought to be responsible for tumor recurrence. In this study, we demonstrated that CSC and chemoresistant cells derived from triple negative breast cancer cells display an enrichment of up- and downregulated proteins from metabolic pathways that suggests their dependence on mitochondria for survival. Here, we selected antibiotics, in particular - linezolid, inhibiting translation of mitoribosomes and inducing mitochondrial dysfunction. We provided the first in vivo evidence demonstrating that linezolid suppressed tumor growth rate, accompanied by increased autophagy. In addition, our results revealed that bactericidal antibiotics used in combination with autophagy blocker decrease tumor growth. This study puts mitochondria in a spotlight for cancer therapy and places antibiotics as effective agents for eliminating CSC and resistant cells.
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$a García-Mayea, Yoelsis $u From the ‡Biomedical Research in Cancer Stem Cell Group, Pathology Department, Vall d'Hebron Hospital, 08035, Passeig Vall d'Hebron 119-129, 08035 Barcelona. Barcelona, Spain.
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$a Mir, Cristina $u From the ‡Biomedical Research in Cancer Stem Cell Group, Pathology Department, Vall d'Hebron Hospital, 08035, Passeig Vall d'Hebron 119-129, 08035 Barcelona. Barcelona, Spain.
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$a Sebastian, David $u §Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain 08028. ¶Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, c/ Baldiri Reixac, 10-12, Barcelona 08028, Spain. ‖CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid 28029, Spain.
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$a Zorzano, Antonio $u §Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain 08028. ¶Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, c/ Baldiri Reixac, 10-12, Barcelona 08028, Spain. ‖CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid 28029, Spain.
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$a Potesil, David $u **CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
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$a Zdrahal, Zbynek $u **CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic. ‡‡National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic.
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$a Lyakhovich, Alex $u From the ‡Biomedical Research in Cancer Stem Cell Group, Pathology Department, Vall d'Hebron Hospital, 08035, Passeig Vall d'Hebron 119-129, 08035 Barcelona. Barcelona, Spain; alex.lyakhovich@vhir.org.
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$a Lleonart, Matilde E $u From the ‡Biomedical Research in Cancer Stem Cell Group, Pathology Department, Vall d'Hebron Hospital, 08035, Passeig Vall d'Hebron 119-129, 08035 Barcelona. Barcelona, Spain; matilde.lleonart@vhir.org. §§Spanish Biomedical Research Network Centre in Oncology, CIBERONC, Barcelona, Spain.
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