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Cited by 155PI3K/AKT/mTOR signaling in cancerWnt/β-catenin signaling in development and cancerCancer, Hypoxia, and Metabolism

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

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Adebayo Michael, Adeola O., Ko, Sungjin, Tao, Junyan, Moghe, Akshata, Yang, Hong, Xu, Meng, Russell, Jacquelyn O., Pradhan-Sundd, Tirthadipa +17 more·2019·Cell Metabolism
DOI 10.1016/j.cmet.2019.01.002PMC PMC6506359
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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.

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  • Previous studies have shown that cells in zone 3 can transform into HCC.

    “Previous studies have shown that cells in zone 3 can transform into HCC (22–24), but there has not been a head-to-head comparison to assess cancer formation from different zones.”

    From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [22]

    The Introduction describes β-catenin activity in zone-3 hepatocytes and β-catenin mutations in some HCCs. The Results localize GS and p-mTOR-S2448 to zone-3 hepatocytes in normal liver, but neither passage establishes that those cells transformed into HCC. Searches for pericentral HCC origin and zone-3 tumor initiation found no passage demonstrating that transition. (LLM, conf=0.72)

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Authors
Adebayo Michael, A. O., Ko, S., Tao, J., Moghe, A., Yang, H., Xu, M., Russell, J. O., Pradhan-Sundd, T., Liu, S., Singh, S., Poddar, M., Monga, J. S., Liu, P., Oertel, M., Ranganathan, S., Singhi, A., Rebouissou, S., Zucman-Rossi, J., Ribback, S., Calvisi, D., Qvartskhava, N., Görg, B., Häussinger, D., Chen, X., & Monga, S. P.
Affiliations
  • University of Pittsburgh (US)
  • Guangxi Medical University (CN)
  • University of California, San Francisco (US)
  • Inserm (FR)
  • Universität Greifswald (DE)
  • Heinrich Heine University Düsseldorf (DE)
Corresponding author
Monga, Satdarshan P.
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2019-05
Volume
29
Issue
5
Pages
1135-1150.e6
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2019.01.002
PMC
PMC6506359
OpenAlex
W2913664928
Cited by
155
References
56
Citations by year
2026: 13 · 2025: 15 · 2024: 40 · 2023: 17 · 2022: 20 · 2021: 21 · 2020: 11 · 2019: 18
FWCI
5.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • UnissResearch (Università degli Studi di Sassari) (submittedVersion, cc-by)
Funders
  • NIH (1R01DK62277, 1R01DK100287, 1R01DK116993, T32CA186873, R01CA204586)
  • Deutsche Forschungsgemeinschaft (SFB 974)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
mTORC1 inhibition, CTNNB1 mutation, glutamine synthetase, hepatocellular carcinoma, Wnt signaling, pericentral hepatocytes, liver cancer, glutamine metabolism, cell proliferation, cell survival
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Acetates, Animals, Cell Survival, Child, Child, Preschool, Disease Models, Animal, Female, Glutamine, Glutamate-Ammonia Ligase, Carcinoma, Hepatocellular, Humans, Infant, Liver Neoplasms, Male, Mice, Inbred C57BL, Mutation, Phenols, Retrospective Studies, Transfection, Mice, Knockout, Sirolimus, Hepatocytes, Cell Line, Tumor, Cell Proliferation, beta Catenin, Mice, TOR Serine-Threonine Kinases, Wnt Signaling Pathway

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