Glutamine synthetase mediates sorafenib sensitivity in β-catenin-active hepatocellular carcinoma cells

Exp Mol Med. 2018 Jan 5;50(1):e421. doi: 10.1038/emm.2017.174.


The gene encoding β-catenin is frequently mutated in hepatocellular carcinoma cells. While the oncogenicity of β-catenin has been extensively studied, β-catenin's role in hepatocellular carcinoma tumor metabolism is currently less well understood. In this study, we found that β-catenin regulates the expression of glutamine synthetase and triggers a series of metabolic changes leading to induction of autophagy in hepatocellular carcinoma cells. β-Catenin-active Hep3B and HepG2 cells exhibited higher basal levels of autophagic activity than did β-catenin wild-type cells. We also found that autophagy in β-catenin-active cells was mediated by glutamine synthetase, as silencing of glutamine synthetase significantly reduced autophagic activity. We also showed that β-catenin-active hepatocellular carcinoma cells were more sensitive to sorafenib than were β-catenin wild-type cells. Our results demonstrated that glutamine synthetase-mediated autophagy explains the high sensitivity of β-catenin-active hepatocellular carcinoma cells to sorafenib. Our results highlight the importance of glutamine metabolism in the regulation of autophagy in hepatocellular carcinoma cells. More importantly, our study unravels the molecular mechanisms leading to sorafenib sensitivity in hepatocellular carcinoma.

Publication types

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

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Autophagy / drug effects
  • Autophagy / physiology
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Cell Line, Tumor
  • Glutamate-Ammonia Ligase / genetics
  • Glutamate-Ammonia Ligase / metabolism*
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism
  • Sorafenib / pharmacology*
  • beta Catenin / metabolism*


  • Antineoplastic Agents
  • CTNNB1 protein, human
  • beta Catenin
  • Sorafenib
  • Glutamate-Ammonia Ligase