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

Adebayo Michael, A.; Ko, S.; Tao, J.; Moghe, A.; Yang, H.; Xu, M.; Russell, J.; Pradhan-Sundd, T.; Liu, S.; Singh, S.; Poddar, M.; Monga, J.; 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.

doi:10.1016/j.cmet.2019.01.002

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.

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Titolo:	Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations
Autori:	Adebayo Michael, A. Ko, S. Tao, J. Moghe, A. Yang, H. Xu, M. Russell, J. Pradhan-Sundd, T. Liu, S. Singh, S. Poddar, M. Monga, J. Liu, P. Oertel, M. Ranganathan, S. Singhi, A. Rebouissou, S. Zucman-Rossi, J. Ribback, S. CALVISI, Diego Francesco Qvartskhava, N. Görg, B. Häussinger, D. Chen, X. Monga, S. mostra contributor esterni nascondi contributor esterni
Data di pubblicazione:	2019
Rivista:	CELL METABOLISM
Handle:	http://hdl.handle.net/11388/224824
Appare nelle tipologie:	1.1 Articolo in rivista

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