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Nature cell biology, 2020-02, Vol.22 (2), p.167

2020

Autor(en) / Beteiligte

Titel

BCAT2-mediated BCAA catabolism is critical for development of pancreatic ductal adenocarcinoma

Ist Teil von

Ort / Verlag

England

Erscheinungsjahr

2020

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

Branched-chain amino acid (BCAA) metabolism is potentially linked with development of pancreatic ductal adenocarcinoma (PDAC) . 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 PDAC . 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-Kras ; 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.

Sprache: Englisch
Identifikatoren: eISSN: 1476-4679
DOI: 10.1038/s41556-019-0455-6
Titel-ID: cdi_pubmed_primary_32029896

Format: –
Schlagworte: Adenocarcinoma - genetics, Adenocarcinoma - metabolism, Adenocarcinoma - pathology, Adult, Amino Acids, Branched-Chain - metabolism, Amino Acids, Branched-Chain - pharmacology, Animals, Carcinogenesis - genetics, Carcinogenesis - metabolism, Carcinogenesis - pathology, Carcinoma, Pancreatic Ductal - genetics, Carcinoma, Pancreatic Ductal - metabolism, Carcinoma, Pancreatic Ductal - pathology, Cell Line, Tumor, Disease Progression, Female, Gene Expression Regulation, Neoplastic, Heterografts, Humans, Isoenzymes - genetics, Isoenzymes - metabolism, Keto Acids - metabolism, Keto Acids - pharmacology, Male, Mice, Mice, Transgenic, Middle Aged, Minor Histocompatibility Antigens - genetics, Minor Histocompatibility Antigens - metabolism, Organoids - drug effects, Organoids - metabolism, Organoids - pathology, Pancreatic Ducts - drug effects, Pancreatic Ducts - metabolism, Pancreatic Ducts - pathology, Pancreatic Neoplasms - genetics, Pancreatic Neoplasms - metabolism, Pancreatic Neoplasms - pathology, Pregnancy Proteins - genetics, Pregnancy Proteins - metabolism, Proto-Oncogene Proteins p21(ras) - genetics, Proto-Oncogene Proteins p21(ras) - metabolism, Ribonucleoproteins - genetics, Ribonucleoproteins - metabolism, Signal Transduction, Syk Kinase - genetics, Syk Kinase - metabolism, Transaminases - genetics, Transaminases - metabolism

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