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Targeting Mitochondrial Iron Metabolism Suppresses Tumor Growth and Metastasis by Inducing Mitochondrial Dysfunction and Mitophagy
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SYSNO ASEP 0548987 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Targeting Mitochondrial Iron Metabolism Suppresses Tumor Growth and Metastasis by Inducing Mitochondrial Dysfunction and Mitophagy Author(s) Sandoval-Acuna, Cristian (BTO-N)
Torrealba, Natalia (BTO-N)
Tomkova, Veronika (BTO-N)
Jadhav, Sukanya B. (BTO-N)
Blažková, Kristýna (BTO-N)
Merta, L. (CZ)
Lettlová, Sandra (BTO-N)
Adamcová, Miroslava Kari (UMG-J)
Rosel, D. (CZ)
Brabek, J. (CZ)
Neužil, Jiří (BTO-N) RID
Štursa, Jan (BTO-N)
Werner, Lukáš (BTO-N)
Truksa, Jaroslav (BTO-N) RID, ORCIDNumber of authors 14 Source Title Cancer Research. - : American Association for Cancer Research - ISSN 0008-5472
Roč. 81, č. 9 (2021), s. 2289-2303Number of pages 15 s. Language eng - English Country US - United States Keywords sulfur cluster ; cancer ; biogenesis ; breast ; cells Subject RIV FD - Oncology ; Hematology OECD category Oncology Subject RIV - cooperation Institute of Molecular Genetics - Oncology ; Hematology R&D Projects GA16-12816S GA ČR - Czech Science Foundation (CSF) GA18-13103S GA ČR - Czech Science Foundation (CSF) GC17-01192J GA ČR - Czech Science Foundation (CSF) GA18-10832S GA ČR - Czech Science Foundation (CSF) Method of publishing Limited access Institutional support BTO-N - RVO:86652036 ; UMG-J - RVO:68378050 UT WOS 000647325600005 EID SCOPUS 85105525103 DOI 10.1158/0008-5472.CAN-20-1628 Annotation Deferoxamine (DFO) represents a widely used iron chelator for the treatment of iron overload. Here we describe the use of mitochondrially targeted deferoxamine (mitoDFO) as a novel approach to preferentially target cancer cells. The agent showed marked cytostatic, cytotoxic, and migrastatic properties in vitro, and it significantly suppressed tumor growth and metastasis in vivo. The underlying molecular mechanisms included (I) impairment of [Fe-S] cluster/heme biogenesis, leading to destabilization and loss of activity of [Fe-S] cluster/heme containing enzymes, (II) inhibition of mitochondrial respiration leading to mitochondrial ROS production, resulting in dysfunctional mitochondria with markedly reduced supercomplexes, and (III) fragmentation of the mitochondrial network and induction of mitophagy. Mitochondrial targeting of DFO represents a way to deprive cancer cells of biologically active iron, which is incompatible with their proliferation and invasion, without disrupting systemic iron metabolism. Our findings highlight the importance of mitochondrial iron metabolism for cancer cells and demonstrate repurposing deferoxamine into an effective anti-cancer drug via mitochondrial targeting. Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2022 Electronic address https://cancerres.aacrjournals.org/content/81/9/2289
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