Journal Article

mTORC1-mediated translational elongation limits intestinal tumour initiation and growth

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

2015

Overview

The mTORC1 complex has been implicated in tumorigenesis owing partially to its ability to increase protein translation; now, mTORC1 activity in the mouse intestine is shown not to be required for normal homeostasis but to be necessary for the triggering of tumorigenesis by APC mutations, suggesting that it could be a good target for the prevention of colorectal cancer in high-risk patients. How mTORC sustains tumour growth The mTORC1 complex, a protein kinase complex found in all eukaryotic cells, has been implicated in tumorigenesis because it is known to stimulate protein translation. The main effector pathway downstream of mTORC1 is thought to be 4EBP1, which promotes initiation of translation. William Faller et al . now show that in the mouse intestine, mTORC1 activity is not required for normal homeostasis, but is absolutely required for intestinal tumour formation triggered by APC tumour suppressor gene mutations. The authors identify increased translational elongation downstream of S6 kinase via the elongation factor eEF2 as a requirement for proliferation in APC-deficient but not normal cells. This suggests that translational elongation, rather than initiation, is limiting to cancer cell proliferation in vivo . These findings raise the possibility that targeting mTORC1 signalling may be beneficial in prevention of colorectal cancers in high-risk patients. Inactivation of APC is a strongly predisposing event in the development of colorectal cancer 1 , 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 growth 3 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/51 / 631/337/574 / 631/67 / 631/67/1059/99 / 631/67/70 / 64/60 / 96/106 / Adenomatous Polyposis Coli Protein - deficiency / Adenomatous Polyposis Coli Protein - genetics / Analysis / Animals / Apoptosis / Cell Proliferation / Cell Transformation, Neoplastic - metabolism / Cell Transformation, Neoplastic - pathology / Colorectal cancer / Colorectal carcinoma / Development and progression / Diagnosis / Drug therapy / Elongation Factor 2 Kinase - deficiency / Elongation Factor 2 Kinase - genetics / Elongation Factor 2 Kinase - metabolism / Enzyme Activation / Genes, APC / Humanities and Social Sciences / Inactivation / Intestinal Neoplasms - genetics / Intestinal Neoplasms - metabolism / Intestinal Neoplasms - pathology / Kinases / letter / Male / Mechanistic Target of Rapamycin Complex 1 / Mice / Mice, Inbred C57BL / multidisciplinary / Multiprotein Complexes - metabolism / Oncogene Protein p55(v-myc) - metabolism / Peptide Chain Elongation, Translational / Peptide Elongation Factor 2 - metabolism / Phosphorylation / Protein biosynthesis / Protein synthesis / Proteins / Ribosomal Protein S6 Kinases - metabolism / Rodents / Science / Signal Transduction / Studies / TOR Serine-Threonine Kinases - metabolism / Tumorigenesis / Tumors / Wnt Proteins - metabolism