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Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition

Umemura, A. and Park, E. J. and Taniguchi, K. and Lee, J. H. and Shalapour, S. and Valasek, M. A. and Aghajan, M. and Nakagawa, H. and Seki, E. and Hall, M. N. and Karin, M.. (2014) Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition. Cell metabolism, Vol. 20, H. 1. pp. 133-144.

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Official URL: http://edoc.unibas.ch/dok/A6271966

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Abstract

Obesity can result in insulin resistance, hepatosteatosis, and nonalcoholic steatohepatitis (NASH) and increases liver cancer risk. Obesity-induced insulin resistance depends, in part, on chronic activation of mammalian target of rapamycin complex 1 (mTORC1), which also occurs in human and mouse hepatocellular carcinoma (HCC), a frequently fatal liver cancer. Correspondingly, mTORC1 inhibitors have been considered as potential NASH and HCC treatments. Using a mouse model in which high-fat diet enhances HCC induction by the hepatic carcinogen DEN, we examined whether mTORC1 inhibition attenuates liver inflammation and tumorigenesis. Notably, rapamycin treatment or hepatocyte-specific ablation of the specific mTORC1 subunit Raptor resulted in elevated interleukin-6 (IL-6) production, activation of signal transducer and activator of transcription 3 (STAT3), and enhanced HCC development, despite a transient reduction in hepatosteatosis. These results suggest that long-term rapamycin treatment, which also increases IL-6 production in humans, is unsuitable for prevention or treatment of obesity-promoted liver cancer.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
UniBasel Contributors:Hall, Michael N.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Cell Press
ISSN:1550-4131
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:12 Sep 2014 08:02
Deposited On:18 Jul 2014 09:10

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