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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Ericksen, RE; Lim, SL; McDonnell, E; Shuen, WH; Vadiveloo, M; White, PJ; Ding, Z; Kwok, R; Lee, P; Radda, GK; Toh, HC; Hirschey, MD; Han, W

Published Date

  • May 7, 2019

Published In

Volume / Issue

  • 29 / 5

Start / End Page

  • 1151 - 1165.e6

PubMed ID

  • 30661928

Pubmed Central ID

  • 30661928

Electronic International Standard Serial Number (EISSN)

  • 1932-7420

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2018.12.020

Language

  • eng

Conference Location

  • United States