Targeting Mitochondrial Iron Metabolism Suppresses Tumor Growth and Metastasis by Inducing Mitochondrial Dysfunction and Mitophagy

0548987 - BTÚ 2022 RIV US eng J - Journal Article
Sandoval-Acuna, Cristian - Torrealba, Natalia - Tomkova, Veronika - Jadhav, Sukanya B. - Blažková, Kristýna - Merta, L. - Lettlová, Sandra - Adamcová, Miroslava Kari - Rosel, D. - Brabek, J. - Neužil, Jiří - Štursa, Jan - Werner, Lukáš - Truksa, Jaroslav
Targeting Mitochondrial Iron Metabolism Suppresses Tumor Growth and Metastasis by Inducing Mitochondrial Dysfunction and Mitophagy.
Cancer Research. Roč. 81, č. 9 (2021), s. 2289-2303. ISSN 0008-5472. E-ISSN 1538-7445
R&D Projects: GA ČR(CZ) GA16-12816S; GA ČR(CZ) GA18-13103S; GA ČR(CZ) GC17-01192J; GA ČR(CZ) GA18-10832S
Institutional support: RVO:86652036 ; RVO:68378050
Keywords : sulfur cluster * cancer * biogenesis * breast * cells
OECD category: Oncology; Oncology (UMG-J)
Impact factor: 13.312, year: 2021
Method of publishing: Limited access
https://cancerres.aacrjournals.org/content/81/9/2289

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.
Permanent Link: http://hdl.handle.net/11104/0325023