edoc

mTORC1-mediated translational elongation limits intestinal tumour initiation and growth

Faller, W. J. and Jackson, T. J. and Knight, J. R. P. and Ridgway, R. A. and Jamieson, T. and Karim, S. A. and Jones, C. and Radulescu, S. and Huels, D. J. and Myant, K. B. and Dudek, K. M. and Casey, H. A. and Scopelliti, A. and Cordero, J. B. and Vidal, M. and Pende, M. and Ryazanov, A. G. and Sonenberg, N. and Meyuhas, O. and Hall, M. N. and Bushell, M. and Willis, A. E. and Sansom, O. J.. (2015) mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature, 517 (7535). pp. 497-500.

Full text not available from this repository.

Official URL: http://edoc.unibas.ch/dok/A6319317

Downloads: Statistics Overview

Abstract

Inactivation of APC is a strongly predisposing event in the development of colorectal cancer, prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth, and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1-S6K-eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal 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:Macmillan
ISSN:0028-0836
e-ISSN:1476-4687
Note:Publication type according to Uni Basel Research Database: Journal article
Related URLs:
Identification Number:
Last Modified:13 Dec 2017 09:22
Deposited On:10 Apr 2015 09:12

Repository Staff Only: item control page