ArticleHepatology (Baltimore, Md.)2015
4EBP1/eIF4E and p70S6K/RPS6 axes play critical and distinct roles in hepatocarcinogenesis driven by AKT and N-Ras proto-oncogenes in mice.
Article in Hepatology (Baltimore, Md.), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 88 citations in OpenAlex.
- Article
- Discovery of a small-molecule inhibitor of eIF4E suppressing tumor proliferation via lipid metabolic reprogramming.Journal of advanced research · 2026Article
- Targeting the 4EBP1/HSP90β/Nrf2 Axis Sensitizes β-catenin-mutant Hepatocellular Carcinoma to mTOR Inhibitors via Ferroptosis Induction.Journal of clinical and translational hepatology · 2026Article
- Lactate-driven pyrimidine synthesis promotes ferroptosis resistance in hepatocellular carcinoma.Molecular biomedicine · 2026Article
- Decoding amino acid metabolism in hepatocellular carcinoma: critical nodes and novel therapeutic strategy.Frontiers in oncology · 2026Review
- Purinergic signal transduction and metabolic regulation by ENTPD5 and ENTPD6.Frontiers in endocrinology · 2026Review
- Inhibition of GSK3 and TSC2 Mediates the Oncogenic Activity of AKT in Hepatocellular Carcinoma.Cancer research · 2025Article
- RPL35A Downregulation Suppresses Hepatocellular Carcinoma Cell Proliferation via NCAPG2 Inactivation.Cancer medicine · 2025Article
- Knockout of the Carbohydrate Responsive Element Binding Protein Enhances Proliferation and Tumorigenesis in Renal Tubules of Mice.International journal of molecular sciences · 2024Article
- Identification of Novel PI3Kα Inhibitor Against Gastric Cancer: QSAR-, Molecular Docking-, and Molecular Dynamics Simulation-Based Analysis.Applied biochemistry and biotechnology · 2024Article
- TSC/mTORC1 mediates mTORC2/AKT1 signaling in c-MYC-induced murine hepatocarcinogenesis via centromere protein M.The Journal of clinical investigation · 2024Article
- TIPRL, a Potential Double-edge Molecule to be Targeted and Re-targeted Toward Cancer.Cell biochemistry and biophysics · 2024Review
- DAP3 promotes mitochondrial activity and tumour progression in hepatocellular carcinoma by regulating MT-ND5 expression.Cell death & disease · 2024Article
- Targeting vimentin: a multifaceted approach to combatting cancer metastasis and drug resistance.Cancer metastasis reviews · 2024Review
- RBM45 reprograms lipid metabolism promoting hepatocellular carcinoma via Rictor and ACSL1/ACSL4.Oncogene · 2024Article
- Hu-lu-su-pian ameliorates hepatic steatosis by regulating CIDEA expression in AKT-driven MASLD mice.Frontiers in pharmacology · 2024Article
- mTOR Signaling: Roles in Hepatitis B Virus Infection and Hepatocellular Carcinoma.International journal of biological sciences · 2024Review
- Transcription factor Zhx2 is a checkpoint that programs macrophage polarization and antitumor response.Cell death and differentiation · 2023Article
- Application of multi-modality MRI-based radiomics in the pre-treatment prediction of RPS6K expression in hepatocellular carcinoma.Molecular biomedicine · 2023Article
- Translational Control of Metabolism and Cell Cycle Progression in Hepatocellular Carcinoma.International journal of molecular sciences · 2023Review
1 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 4 institutions in 3 countries.
Funding
Abstract
unlabelledConcomitant expression of activated forms of v-akt murine thymoma viral oncogene homolog (AKT) and Ras in mouse liver (AKT/Ras) leads to rapid tumor development through strong activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. mTORC1 functions by regulating p70S6K/ribosomal protein S6 (RPS6) and eukaryotic translation initiation factor 4E-binding protein 1/ eukaryotic translation initiation factor 4E (4EBP1/eIF4E) cascades. How these cascades contribute to hepatocarcinogenesis remains unknown. Here, we show that inhibition of the RPS6 pathway by rapamycin effectively suppressed, whereas blockade of the 4EBP1/eIF4E cascade by 4EBP1A4, an unphosphorylatable form of 4EBP1, significantly delayed, AKT/Ras-induced hepatocarcinogenesis. Combined treatment with rapamycin and 4EBP1A4 completely inhibited AKT/Ras hepatocarcinogenesis. This strong antineoplastic effect was successfully recapitulated by ablating regulatory associated protein of mTORC1, the major subunit of mTORC1, in AKT/Ras-overexpressing livers. Furthermore, we demonstrate that overexpression of eIF4E, the proto-oncogene whose activity is specifically inhibited by 4EBP1, resulted in hepatocellular carcinoma (HCC) development in cooperation with activated Ras. Mechanistically, we identified the ectonucleoside triphosphate diphosphohydrolase 5/ adenylate kinase 1/cytidine monophosphate kinase 1 axis and the mitochondrial biogenesis pathway as targets of the 4EBP1/eIF4E cascade in AKT/Ras and Ras/eIF4E livers as well as in human HCC cell lines and tissues.
conclusionsComplete inhibition of mTORC1 is required to suppress liver cancer development induced by AKT and Ras proto-oncogenes in mice. The mTORC1 effectors, RPS6 and eIF4E, play distinct roles and are both necessary for AKT/Ras hepatocarcinogenesis. These new findings might open the way for innovative therapies against human HCC.
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