mTORC1-mediated translational elongation limits intestinal tumour initiation and growth.

Authors
Faller, William J 
Jackson, Thomas J 
Knight, John Rp 
Ridgway, Rachel A 
Jamieson, Thomas 

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Article
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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.

Publication Date
2015-01-22
Online Publication Date
2014-11-05
Acceptance Date
2014-09-26
Keywords
Adenomatous Polyposis Coli Protein, Animals, Cell Proliferation, Cell Transformation, Neoplastic, Elongation Factor 2 Kinase, Enzyme Activation, Genes, APC, Intestinal Neoplasms, Male, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Multiprotein Complexes, Oncogene Protein p55(v-myc), Peptide Chain Elongation, Translational, Peptide Elongation Factor 2, Ribosomal Protein S6 Kinases, Signal Transduction, TOR Serine-Threonine Kinases, Wnt Proteins
Journal Title
Nature
Journal ISSN
0028-0836
1476-4687
Volume Title
517
Publisher
Springer Science and Business Media LLC