Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations

Cell Metab. 2019 May 7;29(5):1135-1150.e6. doi: 10.1016/j.cmet.2019.01.002. Epub 2019 Jan 31.

Abstract

Based on their lobule location, hepatocytes display differential gene expression, including pericentral hepatocytes that surround the central vein, which are marked by Wnt-β-catenin signaling. Activating β-catenin mutations occur in a variety of liver tumors, including hepatocellular carcinoma (HCC), but no specific therapies are available to treat these tumor subsets. Here, we identify a positive relationship between β-catenin activation, its transcriptional target glutamine synthetase (GS), and p-mTOR-S2448, an indicator of mTORC1 activation. In normal livers of mice and humans, pericentral hepatocytes were simultaneously GS and p-mTOR-S2448 positive, as were β-catenin-mutated liver tumors. Genetic disruption of β-catenin signaling or GS prevented p-mTOR-S2448 expression, while its forced expression in β-catenin-deficient livers led to ectopic p-mTOR-S2448 expression. Further, we found notable therapeutic benefit of mTORC1 inhibition in mutant-β-catenin-driven HCC through suppression of cell proliferation and survival. Thus, mTORC1 inhibitors could be highly relevant in the treatment of liver tumors that are β-catenin mutated and GS positive.

Keywords: Wnt; beta-catenin; glutamine synthetase; hepatocellular cancer; liver tumor; mTOR; metabolic zonation; personalized medicine; precision therapy; tumor metabolism.

Publication types

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

MeSH terms

  • Acetates / pharmacology
  • Acetates / therapeutic use
  • Animals
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Child
  • Child, Preschool
  • Disease Models, Animal
  • Female
  • Glutamate-Ammonia Ligase / genetics
  • Glutamate-Ammonia Ligase / metabolism
  • Glutamine / metabolism*
  • Hepatocytes / metabolism
  • Humans
  • Infant
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / metabolism*
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation*
  • Phenols / pharmacology
  • Phenols / therapeutic use
  • Retrospective Studies
  • Sirolimus / pharmacology
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases / genetics
  • Transfection
  • Wnt Signaling Pathway / genetics
  • beta Catenin / genetics*
  • beta Catenin / metabolism

Substances

  • Acetates
  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • GC 1 compound
  • Phenols
  • beta Catenin
  • Glutamine
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Glutamate-Ammonia Ligase
  • Sirolimus