Targeting Mitochondrial Iron Metabolism Suppresses Tumor Growth and Metastasis by Inducing Mitochondrial Dysfunction and Mitophagy
| العنوان: | Targeting Mitochondrial Iron Metabolism Suppresses Tumor Growth and Metastasis by Inducing Mitochondrial Dysfunction and Mitophagy |
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| المؤلفون: | Ladislav Merta, Natalia Torrealba, Jaroslav Truksa, Jan Stursa, Jiri Neuzil, Lukas Werner, Daniel Rösel, Veronika Tomkova, Kristyna Blazkova, Jan Brábek, Sandra Lettlova, Sukanya Balkrishna Jadhav, Miroslava Kari Adamcová, Cristian Sandoval-Acuña |
| المصدر: | Cancer Research. 81:2289-2303 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Programmed cell death, Carcinogenesis, Iron, Heme, Deferoxamine, Mitochondrion, Iron Chelating Agents, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cell Movement, Neoplasms, Mitophagy, medicine, Animals, Humans, Cell Proliferation, chemistry.chemical_classification, Mice, Inbred BALB C, Reactive oxygen species, Cell Death, Chemistry, Xenograft Model Antitumor Assays, Mitochondria, Tumor Burden, Cell biology, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, PC-3 Cells, Cancer cell, MCF-7 Cells, Reactive Oxygen Species, Biogenesis, Signal Transduction, medicine.drug |
| الوصف: | 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 iron-sulfur [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 reactive oxygen species production, resulting in dysfunctional mitochondria with markedly reduced supercomplexes, and (iii) fragmentation of the mitochondrial network and induction of mitophagy. Mitochondrial targeting of deferoxamine 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 anticancer drug via mitochondrial targeting. Significance: These findings show that targeting the iron chelator deferoxamine to mitochondria impairs mitochondrial respiration and biogenesis of [Fe-S] clusters/heme in cancer cells, which suppresses proliferation and migration and induces cell death. |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e1e1541bc5830526b4b0452ad972a170 https://doi.org/10.1158/0008-5472.can-20-1628 |
| رقم الأكسشن: | edsair.doi.dedup.....e1e1541bc5830526b4b0452ad972a170 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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