Chemoproteomic Profiling Reveals Ethacrynic Acid Targets Adenine Nucleotide Translocases to Impair Mitochondrial Function.
Mol Pharm
; 15(6): 2413-2422, 2018 06 04.
Article
en En
| MEDLINE
| ID: mdl-29763317
ABSTRACT
Ethacrynic acid (EA) is a diuretic drug that is widely used to treat high-blood pressure and swelling caused by congestive heart failure or kidney failure. It acts through noncovalent inhibition of the Na+-K+-2Cl- cotransporter in the thick ascending limb of Henle's loop. Chemically, EA contains a Michael acceptor group that can react covalently with nucleophilic residues in proteins; however, the proteome reactivity of EA remains unexplored. Herein, we took a quantitative chemoproteomic approach to globally profile EA's targets in cancer cells. We discovered that EA induces impaired mitochondrial function accompanied by increased ROS production. Our profiling revealed that EA targets functional proteins on mitochondrial membranes, including adenine nucleotide translocases (ANTs). Site-specific mapping identified that EA covalently modifies a functional cysteine in ANTs, a mutation of which resulted in the rescuing effect on EA-induced mitochondrial dysfunction. The newly discovered modes of action offer valuable information to repurpose EA for cancer treatment.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Translocasas Mitocondriales de ADP y ATP
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Ácido Etacrínico
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Reposicionamiento de Medicamentos
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Mitocondrias
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Neoplasias
Límite:
Humans
Idioma:
En
Año:
2018
Tipo del documento:
Article