Journal article
mTORC1 inhibition restricts infammation-associated gastrointestinal tumorigenesis in mice
S Thiem, TP Pierce, M Palmieri, TL Putoczki, M Buchert, A Preaudet, RO Farid, C Love, B Catimel, Z Lei, S Rozen, V Gopalakrishnan, F Schaper, M Hallek, A Boussioutas, P Tan, A Jarnicki, M Ernst
Journal of Clinical Investigation | AMER SOC CLINICAL INVESTIGATION INC | Published : 2013
DOI: 10.1172/JCI65086
Abstract
Gastrointestinal 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..
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Awarded by National Health and Medical Research Council Australia (NHMRC)
Awarded by Deutsche Forschungsgemeinschaft
Funding Acknowledgements
We thank Rachel Hughan, Christine Dijkstra, Elsbeth Richardson, Valarie Feakes, Cary Tsui, and the LICR animal facility staff for expert technical assistance. We thank Stefan Rose-John (Christian-Albrechts-Universitat zu Kiel) for recombinant IL-6 and hyper-IL-6, Lorraine Robb (Walter and Eliza Hall Institute) for recombinant IL-11, and Nick Wilson (CSL Limited, Melbourne, Australia) for providing IL-11R alpha-expressing BaF3 cells. We are grateful to Florian Greten. and Joan Heath for helpful discussions. This work was supported by funds from the Operational Infrastructure Support Program provided by the Victorian Government (Australia) and the following grants from the National Health and Medical Research Council Australia (NHMRC): no. 433617, no. 487922, no. 603122, no. 603132, and no. 1008614. M. Ernst is a Senior Research Fellow of the NHMRC. Work of Michael Hallek was supported by Deutsche Forschungsgemeinschaft SFB 832 (A16). The contents of this material are solely the responsibility of the Administering Institution, Participating Institutions, or individual authors and do not reflect the views of NHMRC.