BCAT2-mediated BCAA catabolism is critical for development of pancreatic ductal adenocarcinoma.
Nat Cell Biol
; 22(2): 167-174, 2020 02.
Article
en En
| MEDLINE
| ID: mdl-32029896
ABSTRACT
Branched-chain amino acid (BCAA) metabolism is potentially linked with development of pancreatic ductal adenocarcinoma (PDAC)1-4. BCAA transaminase 2 (BCAT2) was essential for the collateral lethality conferred by deletion of malic enzymes in PDAC and the BCAA-BCAT metabolic pathway contributed to non-small-cell lung carcinomas (NSCLCs) other than PDAC3,4. However, the underlying mechanism remains undefined. Here we reveal that BCAT2 is elevated in mouse models and in human PDAC. Furthermore, pancreatic tissue-specific knockout of Bcat2 impedes progression of pancreatic intraepithelial neoplasia (PanIN) in LSL-KrasG12D/+; Pdx1-Cre (KC) mice. Functionally, BCAT2 enhances BCAA uptake to sustain BCAA catabolism and mitochondrial respiration. Notably, BCAA enhances growth of pancreatic ductal organoids from KC mice in a dose-dependent manner, whereas addition of branched-chain α-keto acid (BCKA) and nucleobases rescues growth of KC organoids that is suppressed by BCAT2 inhibitor. Moreover, KRAS stabilizes BCAT2, which is mediated by spleen tyrosine kinase (SYK) and E3 ligase tripartite-motif-containing protein 21 (TRIM21). In addition, BCAT2 inhibitor ameliorates PanIN formation in KC mice. Of note, a lower-BCAA diet also impedes PDAC development in mouse models of PDAC. Thus, BCAT2-mediated BCAA catabolism is critical for development of PDAC harbouring KRAS mutations. Targeting BCAT2 or lowering dietary BCAA may have translational significance.
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Base de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
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Proteínas Gestacionales
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Adenocarcinoma
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Regulación Neoplásica de la Expresión Génica
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Antígenos de Histocompatibilidad Menor
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Proteínas Proto-Oncogénicas p21(ras)
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Carcinoma Ductal Pancreático
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Aminoácidos de Cadena Ramificada
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Transaminasas
Idioma:
En
Revista:
Nat Cell Biol
Año:
2020
Tipo del documento:
Article