Please use this identifier to cite or link to this item: https://doi.org/10.1172/JCI65086
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dc.titlemTORC1 inhibition restricts infammation-associated gastrointestinal tumorigenesis in mice
dc.contributor.authorThiem, S.
dc.contributor.authorPierce, T.P.
dc.contributor.authorPalmieri, M.
dc.contributor.authorPutoczki, T.L.
dc.contributor.authorBuchert, M.
dc.contributor.authorPreaudet, A.
dc.contributor.authorFarid, R.O.
dc.contributor.authorLove, C.
dc.contributor.authorCatimel, B.
dc.contributor.authorLei, Z.
dc.contributor.authorRozen, S.
dc.contributor.authorGopalakrishnan, V.
dc.contributor.authorSchaper, F.
dc.contributor.authorHallek, M.
dc.contributor.authorBoussioutas, A.
dc.contributor.authorTan, P.
dc.contributor.authorJarnicki, A.
dc.contributor.authorErnst, M.
dc.date.accessioned2014-11-26T08:29:27Z
dc.date.available2014-11-26T08:29:27Z
dc.date.issued2013-02-01
dc.identifier.citationThiem, S., Pierce, T.P., Palmieri, M., Putoczki, T.L., Buchert, M., Preaudet, A., Farid, R.O., Love, C., Catimel, B., Lei, Z., Rozen, S., Gopalakrishnan, V., Schaper, F., Hallek, M., Boussioutas, A., Tan, P., Jarnicki, A., Ernst, M. (2013-02-01). mTORC1 inhibition restricts infammation-associated gastrointestinal tumorigenesis in mice. Journal of Clinical Investigation 123 (2) : 767-781. ScholarBank@NUS Repository. https://doi.org/10.1172/JCI65086
dc.identifier.issn00219738
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/110180
dc.description.abstractGastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL-6 family cytokines, which promote tumorigenesis through persistent activation of the GP130/JAK/STAT3 pathway. Although tumor progression can be prevented by genetic ablation of Stat3 in mice, this transcription factor remains a challenging therapeutic target with a paucity of clinically approved inhibitors. Here, we uncovered parallel and excessive activation of mTOR complex 1 (mTORC1) alongside STAT3 in human intestinal-type gastric cancers (IGCs). Furthermore, in a preclinical mouse model of IGC, GP130 ligand administration simultaneously activated mTORC1/S6 kinase and STAT3 signaling. We therefore investigated whether mTORC1 activation was required for inflammation-associated gastrointestinal tumorigenesis. Strikingly, the mTORC1-specific inhibitor RAD001 potently suppressed initiation and progression of both murine IGC and colitis-associated colon cancer. The therapeutic effect of RAD001 was associated with reduced tumor vascularization and cell proliferation but occurred independently of STAT3 activity. We analyzed the mechanism of GP130-mediated mTORC1 activation in cells and mice and revealed a requirement for JAK and PI3K activity but not for GP130 tyrosine phosphorylation or STAT3. Our results suggest that GP130-dependent activation of the druggable PI3K/mTORC1 pathway is required for inflammation-associated gastrointestinal tumorigenesis. These findings advocate clinical application of PI3K/mTORC1 inhibitors for the treatment of corresponding human malignancies.
dc.description.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1172/JCI65086
dc.sourceScopus
dc.typeArticle
dc.contributor.departmentDUKE-NUS GRADUATE MEDICAL SCHOOL S'PORE
dc.description.doi10.1172/JCI65086
dc.description.sourcetitleJournal of Clinical Investigation
dc.description.volume123
dc.description.issue2
dc.description.page767-781
dc.description.codenJCINA
dc.identifier.isiut000314553600030
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