Downregulation of PCK2 remodels tricarboxylic acid cycle in tumor-repopulating cells of melanoma.
Oncogene
; 36(25): 3609-3617, 2017 06 22.
Article
en En
| MEDLINE
| ID: mdl-28166201
ABSTRACT
For cancer cells to proliferate, a balance must be built between biomass-forming, glucose-metabolized intermediates and ATP production. How intrinsic glucose carbon flow regulates this balance remains unclear. Here we show that mitochondrial phosphoenolpyruvate carboxykinase (PCK2), the hub molecule linking tricarboxylic acid (TCA) cycle, glycolysis and gluconeogenesis by conversion of mitochondrial oxaloacetate (OAA) to phosphoenolpyruvate, regulates glucose carbon flow direction in stem-like cells that repopulate tumors (tumor-repopulating cells (TRCs)). PCK2 downregulation accelerated biosynthesis and transportation of citrate from mitochondria to the cytosol, leading to cytosolic glucose carbon flow via OAA-malate-pyruvate and acetyl-CoA-fatty acid pathways in TRCs. On the other hand, downregulating PCK2 hindered fumarate carbon flows in TCA cycle, leading to attenuated oxidative phosphorylation. In pathological terms, PCK2 overexpression slowed TRC growth in vitro and impeded tumorigenesis in vivo. Overall, our work unveiled unexpected glucose carbon flows of TRCs in melanoma that have implications for targeting metabolic aspects of melanoma.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Regulación hacia Abajo
/
Regulación Enzimológica de la Expresión Génica
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Regulación Neoplásica de la Expresión Génica
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Ciclo del Ácido Cítrico
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Fosfoenolpiruvato Carboxiquinasa (ATP)
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Melanoma
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Proteínas de Neoplasias
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Oncogene
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Año:
2017
Tipo del documento:
Article
País de afiliación:
China