Targeted inhibition of MCT4 disrupts intracellular pH homeostasis and confers self-regulated apoptosis on hepatocellular carcinoma.
Exp Cell Res
; 384(1): 111591, 2019 11 01.
Article
en En
| MEDLINE
| ID: mdl-31479685
ABSTRACT
The high lactate production rate in hepatocellular carcinoma cells (HCC) have a profound impact on their malignant properties. In adaptation to the enhanced lactate stress, lactate-effusing monocarboxylate transporter 4(MCT4) is usually overexpressed in a broad range of HCC subtypes. In this study, the MCT4-mediated lactate efflux in HCC was blocked using microRNA-145(miR-145), which would force the endogenously generated lactate to accumulate within tumor cells in a self-regulated manner, resulting in the acidification of the cytoplasmic compartment as well as partial neutralization for pH in the tumor extracellular environment. Evaluations on multiple representative HCC subtypes (HepG2, Hep3B and HuH7) suggested that the disrupted pH homeostasis would amplify the lactate stress to initiate HCC apoptosis, while at the same time also suppressing their migration and invasion abilities. Moreover, safety tests on 7702â¯cells and living animals revealed that MCT4-blockade treatment has no cytotoxicity against healthy cells/tissues. The results indicate the MCT4-inhibition-induced disruption of tumor intracellular pH holds promise as a therapy against not only HCC, but a broader spectrum of MCT4-overexpressing hyperglycolytic tumors.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Apoptosis
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Carcinoma Hepatocelular
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Transportadores de Ácidos Monocarboxílicos
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Homeostasis
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Neoplasias Hepáticas
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Proteínas Musculares
Límite:
Animals
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Humans
Idioma:
En
Año:
2019
Tipo del documento:
Article