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

Adeola O. Adebayo Michael, Sungjin Ko, Junyan Tao, Akshata Moghe, Hong Yang, Meng Xu, Jacquelyn O. Russell, Tirthadipa Pradhan-Sundd, Silvia Liu, Sucha Singh, Minakshi Poddar, Jayvir S. Monga, Pin Liu, Michael Oertel, Sarangarajan Ranganathan, Aatur Singhi, Sandra Rebouissou, Jessica Zucman-Rossi, Silvia Ribback, Diego CalvisiNatalia Qvartskhava, Boris Görg, Dieter Häussinger, Xin Chen, Satdarshan P. Monga

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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. Michael, Ko et al. show that β-catenin activation in zone-3 hepatocytes leads to high mTORC1 activity downstream of elevated glutamine synthetase expression and intracellular glutamine. Due to the same reason, liver tumors harboring mutated, hyperactive β-catenin also show mTORC1 activation, making them susceptible to mTOR inhibitors.

Original languageEnglish (US)
Pages (from-to)1135-1150.e6
JournalCell Metabolism
Volume29
Issue number5
DOIs
StatePublished - May 7 2019
Externally publishedYes

Keywords

  • Wnt
  • beta-catenin
  • glutamine synthetase
  • hepatocellular cancer
  • liver tumor
  • mTOR
  • metabolic zonation
  • personalized medicine
  • precision therapy
  • tumor metabolism

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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