Loss of BCAA Catabolism during Carcinogenesis Enhances mTORC1 Activity and Promotes Tumor Development and Progression.
Aged
Aged, 80 and over
Amino Acids, Branched-Chain
/ administration & dosage
Animals
Carcinogenesis
/ drug effects
Carcinoma, Hepatocellular
/ metabolism
Cell Proliferation
/ drug effects
Cohort Studies
Disease Models, Animal
Disease Progression
Down-Regulation
Female
Hep G2 Cells
Humans
Liver Neoplasms
/ metabolism
Male
Mechanistic Target of Rapamycin Complex 1
/ metabolism
Mice
Mice, Inbred C57BL
Middle Aged
Rats
Rats, Inbred ACI
branched-chain amino acids
cancer
cancer metabolism
dietary intake
hepatocellular carcinoma
mTORC1
metabolomics
transcriptomics
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
07 05 2019
07 05 2019
Historique:
received:
30
05
2018
revised:
13
09
2018
accepted:
21
12
2018
pubmed:
22
1
2019
medline:
14
7
2020
entrez:
22
1
2019
Statut:
ppublish
Résumé
Tumors display profound changes in cellular metabolism, yet how these changes aid the development and growth of tumors is not fully understood. Here we use a multi-omic approach to examine liver carcinogenesis and regeneration, and find that progressive loss of branched-chain amino acid (BCAA) catabolism promotes tumor development and growth. In human hepatocellular carcinomas and animal models of liver cancer, suppression of BCAA catabolic enzyme expression led to BCAA accumulation in tumors, though this was not observed in regenerating liver tissues. The degree of enzyme suppression strongly correlated with tumor aggressiveness, and was an independent predictor of clinical outcome. Moreover, modulating BCAA accumulation regulated cancer cell proliferation in vitro, and tumor burden and overall survival in vivo. Dietary BCAA intake in humans also correlated with cancer mortality risk. In summary, loss of BCAA catabolism in tumors confers functional advantages, which could be exploited by therapeutic interventions in certain cancers.
Identifiants
pubmed: 30661928
pii: S1550-4131(18)30757-5
doi: 10.1016/j.cmet.2018.12.020
pmc: PMC6506390
mid: NIHMS1517776
pii:
doi:
Substances chimiques
Amino Acids, Branched-Chain
0
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1151-1165.e6Subventions
Organisme : NCI NIH HHS
ID : P30 CA014236
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG045351
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK115568
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA059365
Pays : United States
Informations de copyright
Copyright © 2018 Elsevier Inc. All rights reserved.
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