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

Autor: Zhi-Gang Zhang, Zheng-Jun Chen, Ming-Zhu Lei, Haojie Lu, Lei Zhang, Yi-Ping Wang, Di Wang, Jian Wang, Qun-Ying Lei, Ying Liu, Miao Yin, Shao-Wu Zou, Dan Su, Wenyu Wen, Ye Zhang, Jin-Tao Li, Li-Peng Hu
Rok vydání: 2020
Předmět:
Male
endocrine system diseases
Carcinogenesis
Pancreatic Intraepithelial Neoplasia
Syk
Pregnancy Proteins
medicine.disease_cause
Mice
0302 clinical medicine
Regulation of gene expression
0303 health sciences
biology
Chemistry
Middle Aged
Keto Acids
Ubiquitin ligase
Cell biology
Gene Expression Regulation
Neoplastic
Isoenzymes
Organoids
Ribonucleoproteins
030220 oncology & carcinogenesis
Disease Progression
Heterografts
Female
KRAS
Signal transduction
Carcinoma
Pancreatic Ductal
Signal Transduction
Adult
Transgene
Mice
Transgenic
Adenocarcinoma
Minor Histocompatibility Antigens
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
Cell Line
Tumor
medicine
Animals
Humans
Syk Kinase
Transaminases
030304 developmental biology
Catabolism
Pancreatic Ducts
Cell Biology
digestive system diseases
Pancreatic Neoplasms
biology.protein
Cancer research
Amino Acids
Branched-Chain
Zdroj: Nature Cell Biology. 22:167-174
ISSN: 1476-4679
1465-7392
Popis: 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.
Databáze: OpenAIRE
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