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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F21%3A00548987" target="_blank" >RIV/86652036:_____/21:00548987 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68378050:_____/21:00548987 RIV/00216208:11310/21:10436885

Výsledek na webu

<a href="https://cancerres.aacrjournals.org/content/81/9/2289" target="_blank" >https://cancerres.aacrjournals.org/content/81/9/2289</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1158/0008-5472.CAN-20-1628" target="_blank" >10.1158/0008-5472.CAN-20-1628</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30204 - Oncology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Cancer Research

ISSN

0008-5472

e-ISSN

1538-7445

Svazek periodika

81

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

15

Strana od-do

2289-2303

Kód UT WoS článku

000647325600005

EID výsledku v databázi Scopus

2-s2.0-85105525103