mTORC1-mediated translational elongation limits intestinal tumour initiation and growth

William J. Faller, Thomas J. Jackson, John R. P. Knight, Rachel A. Ridgway, Thomas Jamieson, Saadia A. Karim, Carolyn Jones, Sorina Radulescu, David J. Huels, Kevin B. Myant, Kate M. Dudek, Helen A. Casey, Alessandro Scopelliti, Julia B. Cordero, Marcos Vidal, Mario Pende, Alexey G. Ryazanov, Nahum Sonenberg, Oded Meyuhas, Michael N. HallMartin Bushell, Anne E. Willis, Owen J. Sansom

Research output: Contribution to journalArticlepeer-review

Abstract

Inactivation of APC is a strongly predisposing event in the development of colorectal cancer1,2, 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 growth3,4,5, 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.
Original languageEnglish
Pages (from-to)497-500
Number of pages4
JournalNature
Volume517
Issue number7535
Early online date5 Nov 2014
DOIs
Publication statusPublished - 22 Jan 2015

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