Loss of BCAA Catabolism during Carcinogenesis Enhances mTORC1 Activity and Promotes Tumor Development and Progression

Cell Metab. 2019 May 7;29(5):1151-1165.e6. doi: 10.1016/j.cmet.2018.12.020. Epub 2019 Jan 17.

Abstract

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.

Keywords: branched-chain amino acids; cancer; cancer metabolism; dietary intake; hepatocellular carcinoma; mTORC1; metabolomics; transcriptomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amino Acids, Branched-Chain / administration & dosage
  • Amino Acids, Branched-Chain / metabolism*
  • Amino Acids, Branched-Chain / pharmacology
  • Animals
  • Carcinogenesis / drug effects
  • Carcinogenesis / metabolism*
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Proliferation / drug effects
  • Cohort Studies
  • Disease Models, Animal
  • Disease Progression*
  • Down-Regulation*
  • Female
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Rats
  • Rats, Inbred ACI

Substances

  • Amino Acids, Branched-Chain
  • Mechanistic Target of Rapamycin Complex 1