mTORC1-mediated translational elongation limits intestinal tumour initiation and growth.
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Autor
Faller, William J
Jackson, Thomas J
Knight, John Rp
Ridgway, Rachel A
Jamieson, Thomas
Karim, Saadia A
Jones, Carolyn
Radulescu, Sorina
Huels, David J
Myant, Kevin B
Dudek, Kate M
Casey, Helen A
Scopelliti, Alessandro
Cordero, Julia B
Vidal, Marcos
Pende, Mario
Ryazanov, Alexey G
Sonenberg, Nahum
Meyuhas, Oded
Hall, Michael N
Bushell, Martin
Sansom, Owen J
Datum
2015-01-22Journal Title
Nature
ISSN
0028-0836
Publisher
Springer Science and Business Media LLC
Volume
517
Issue
7535
Pages
497-500
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Zobrazit celý záznamCitation
Faller, W. J., Jackson, T. J., Knight, J. R., Ridgway, R. A., Jamieson, T., Karim, S. A., Jones, C., et al. (2015). mTORC1-mediated translational elongation limits intestinal tumour initiation and growth.. Nature, 517 (7535), 497-500. https://doi.org/10.1038/nature13896
Abstrakt
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.
Keywords
Animals, Mice, Inbred C57BL, Mice, Intestinal Neoplasms, Cell Transformation, Neoplastic, Multiprotein Complexes, Peptide Elongation Factor 2, Ribosomal Protein S6 Kinases, Adenomatous Polyposis Coli Protein, Oncogene Protein p55(v-myc), Signal Transduction, Cell Proliferation, Enzyme Activation, Peptide Chain Elongation, Translational, Genes, APC, Male, Wnt Proteins, Elongation Factor 2 Kinase, TOR Serine-Threonine Kinases, Mechanistic Target of Rapamycin Complex 1
Identifiers
External DOI: https://doi.org/10.1038/nature13896
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284629
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