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

cam.issuedOnline2014-11-05
dc.contributor.authorFaller, William J
dc.contributor.authorJackson, Thomas J
dc.contributor.authorKnight, John Rp
dc.contributor.authorRidgway, Rachel A
dc.contributor.authorJamieson, Thomas
dc.contributor.authorKarim, Saadia A
dc.contributor.authorJones, Carolyn
dc.contributor.authorRadulescu, Sorina
dc.contributor.authorHuels, David J
dc.contributor.authorMyant, Kevin B
dc.contributor.authorDudek, Kate M
dc.contributor.authorCasey, Helen A
dc.contributor.authorScopelliti, Alessandro
dc.contributor.authorCordero, Julia B
dc.contributor.authorVidal, Marcos
dc.contributor.authorPende, Mario
dc.contributor.authorRyazanov, Alexey G
dc.contributor.authorSonenberg, Nahum
dc.contributor.authorMeyuhas, Oded
dc.contributor.authorHall, Michael N
dc.contributor.authorBushell, Martin
dc.contributor.authorWillis, Anne E
dc.contributor.authorSansom, Owen J
dc.contributor.orcidWillis, Anne [0000-0002-1470-8531]
dc.date.accessioned2018-11-05T10:59:06Z
dc.date.available2018-11-05T10:59:06Z
dc.date.issued2015-01-22
dc.description.abstractInactivation 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.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.32003
dc.identifier.eissn1476-4687
dc.identifier.issn0028-0836
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284629
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/nature13896
dc.subjectAdenomatous Polyposis Coli Protein
dc.subjectAnimals
dc.subjectCell Proliferation
dc.subjectCell Transformation, Neoplastic
dc.subjectElongation Factor 2 Kinase
dc.subjectEnzyme Activation
dc.subjectGenes, APC
dc.subjectIntestinal Neoplasms
dc.subjectMale
dc.subjectMechanistic Target of Rapamycin Complex 1
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMultiprotein Complexes
dc.subjectOncogene Protein p55(v-myc)
dc.subjectPeptide Chain Elongation, Translational
dc.subjectPeptide Elongation Factor 2
dc.subjectRibosomal Protein S6 Kinases
dc.subjectSignal Transduction
dc.subjectTOR Serine-Threonine Kinases
dc.subjectWnt Proteins
dc.titlemTORC1-mediated translational elongation limits intestinal tumour initiation and growth.
dc.typeArticle
dcterms.dateAccepted2014-09-26
prism.endingPage500
prism.issueIdentifier7535
prism.publicationDate2015
prism.publicationNameNature
prism.startingPage497
prism.volume517
rioxxterms.licenseref.startdate2015-01
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1038/nature13896

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