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.
Pubmed ID: 30713111 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This unknown targets Rabbit IgG (H+L)
View all literature mentionsThis unknown targets Mouse IgG (H+L)
View all literature mentionsThis monoclonal targets Ki-67
View all literature mentionsThis polyclonal targets Mouse IgG (H+L)
View all literature mentionsThis unknown targets
View all literature mentionsThis monoclonal targets PCNA (PC10)
View all literature mentionsThis monoclonal targets Glutamine Synthetase
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis monoclonal targets GAPDH
View all literature mentionsThis monoclonal targets Catenin, beta
View all literature mentionsThis monoclonal targets Myc-Tag
View all literature mentionsThis monoclonal targets beta Catenin
View all literature mentionsThis unknown targets Glutamine Synthetase
View all literature mentionsThis monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204)
View all literature mentionsThis monoclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis monoclonal targets p70 S6 Kinase
View all literature mentionsThis monoclonal targets 4E-BP1 (53H11) Rabbit mAb
View all literature mentionsThis polyclonal targets Phospho-p70 S6 Kinase (Thr389)
View all literature mentionsThis monoclonal targets 4E-BP1, phospho (Thr37 / Thr46)
View all literature mentionsThis monoclonal targets mTOR
View all literature mentionsThis monoclonal targets Phospho-S6 Ribosomal Protein (Ser240/244) (D68F8) XP Rabbit mAb
View all literature mentionsThis monoclonal targets mTOR, phospho (Ser2448)
View all literature mentionsThis monoclonal targets Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb
View all literature mentionsThis monoclonal targets S6 Ribosomal Protein
View all literature mentionsThis unknown targets Met
View all literature mentionsThis monoclonal targets Phospho-Stat3 (Tyr705)
View all literature mentionsThis monoclonal targets Phospho-mTOR (Ser2448)
View all literature mentionsThis monoclonal targets Met
View all literature mentionsThis recombinant monoclonal targets Stat3
View all literature mentions