| First Author | Adebayo Michael AO | Year | 2019 |
| Journal | Cell Metab | Volume | 29 |
| Issue | 5 | Pages | 1135-1150.e6 |
| PubMed ID | 30713111 | Mgi Jnum | J:274941 |
| Mgi Id | MGI:6303415 | Doi | 10.1016/j.cmet.2019.01.002 |
| Citation | Adebayo Michael AO, et al. (2019) Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by beta-Catenin Mutations. Cell Metab 29(5):1135-1150.e6 |
| abstractText | Based on their lobule location, hepatocytes display differential gene expression, including pericentral hepatocytes that surround the central vein, which are marked by Wnt-beta-catenin signaling. Activating beta-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 beta-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 beta-catenin-mutated liver tumors. Genetic disruption of beta-catenin signaling or GS prevented p-mTOR-S2448 expression, while its forced expression in beta-catenin-deficient livers led to ectopic p-mTOR-S2448 expression. Further, we found notable therapeutic benefit of mTORC1 inhibition in mutant-beta-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 beta-catenin mutated and GS positive. |
