TGF-ß1 targets Smad, p38 MAPK, and PI3K/Akt signaling pathways to induce PFKFB3 gene expression and glycolysis in glioblastoma cells.
FEBS J
; 284(20): 3437-3454, 2017 10.
Article
em En
| MEDLINE
| ID: mdl-28834297
ABSTRACT
In human cancers, transforming growth factor-ß1 (TGF-ß1) plays a dual role by acting as both a tumor suppressor and a promoter of tumor metastasis. Although TGF-ß1 contributes to the metabolic reprogramming of cancer cells and tumor-associated stromal cells, little is known of the molecular mechanisms connecting this cytokine with enhanced glycolysis. PFKFB3 is a homodymeric bifunctional enzyme, belonging to the family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases, that controls the conversion of fructose-6-phosphate (Fru-6-P) to fructose-2,6-bisphosphate (Fru-2,6-P2 ). This metabolite is important for the dynamic regulation of glycolytic flux by allosterically activating phosphofructokinase-1, a rate-limiting enzyme in glycolysis. The PFKFB3 gene is involved in cell proliferation via its role in carbohydrate metabolism. Here, we studied the mechanisms connecting TGF-ß1, glucose metabolism, and PFKFB3 in glioblastoma cell lines. We demonstrate that TGF-ß1 upregulates PFKFB3 mRNA and protein expression resulting in an increase in fructose 2,6-bisphosphate concentration, glucose uptake, glycolytic flux and lactate production. Moreover, these increases in PFKFB3 mRNA and protein expression and Fru-2,6-P2 concentration were reduced when the Smad3, p38 mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were inhibited. We demonstrate that inhibition of PFKFB3 activity with 3PO or siRNA-mediated knockdown of PFKFB3 significantly eliminated the capacity of the T98G cells to form colonies by TGF-ß1, one of the hallmarks of transformation. Taken together, these results show that TGF-ß1 induces PFKFB3 expression through activation of the p38 MAPK and PI3K/Akt signaling pathways that complement and converge with early activation of Smad signaling. This suggests that PFKFB3 induction by TGF-ß1 can be one of the main mechanisms mediating the reprogramming of glioma cells.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Glioblastoma
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Fosfofrutoquinase-2
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Proteínas Quinases p38 Ativadas por Mitógeno
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Proteínas Proto-Oncogênicas c-akt
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Proteínas Smad
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Fator de Crescimento Transformador beta1
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Inibidores de Fosfoinositídeo-3 Quinase
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Glicólise
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article