Inhibition of mitochondrial translation effectively sensitizes renal cell carcinoma to chemotherapy.
Biochem Biophys Res Commun
; 490(3): 767-773, 2017 08 26.
Article
em En
| MEDLINE
| ID: mdl-28645610
ABSTRACT
The functional importance of mitochondrial protein translation has been recently documented in the context of various cancers but not renal cell carcinoma (RCC). In lines with these efforts, our work demonstrates that mitochondrial translation inhibition by tigecycline or depletion of EF-Tu mitochondrial translation factor effectively targets RCC and significantly sensitizes RCC response to chemotherapy. We show that antibiotic tigecycline inhibits multiple biological functions of RCC, including growth, colony formation and survival. It also significantly enhances in vitro and in vivo efficacy of paclitaxel in RCC. Tigecycline preferentially inhibits translation of mitochondrial DNA-encoded proteins, activities of mitochondrial respiratory complexes that contain mitochondrially encoded subunits. As a consequence of mitochondrial respiratory chain inhibition, decreased mitochondrial respiration is observed in RCC cells exposed to tigecycline. In contrast, tigecycline is ineffective in RCC ρ0 cells that lack mitochondrial DNA and subsequent mitochondrial respiration, further confirm mitochondrial translation inhibition as the mechanism of tigecycline's action in RCC. Importantly, genetic inhibition of mitochondrial translation by EF-Tu knockdown reproduced the inhibitory effects of tigecycline. Finally, we show the association between mitochondrial translation inhibition and suppression of PI3K/Akt/mTOR signaling pathway. Our work used pharmacological and genetic strategies to demonstrate the important roles of mitochondrial translation in RCC and emphasize the therapeutic value of sensitizing RCC to chemotherapy.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Biossíntese de Proteínas
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Carcinoma de Células Renais
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Paclitaxel
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Rim
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Neoplasias Renais
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Minociclina
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Antibacterianos
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Antineoplásicos Fitogênicos
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article