Document Detail

mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice.
MedLine Citation:
PMID:  23321674     Owner:  NLM     Status:  MEDLINE    
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. 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.
Stefan Thiem; Thomas P Pierce; Michelle Palmieri; Tracy L Putoczki; Michael Buchert; Adele Preaudet; Ryan O Farid; Chris Love; Bruno Catimel; Zhengdeng Lei; Steve Rozen; Veena Gopalakrishnan; Fred Schaper; Michael Hallek; Alex Boussioutas; Patrick Tan; Andrew Jarnicki; Matthias Ernst
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-16
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2013-09-30    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  767-81     Citation Subset:  AIM; IM    
Ludwig Institute for Cancer Research, Melbourne-Parkville Branch, Parkville, Victoria, Australia.
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MeSH Terms
Cytokine Receptor gp130 / genetics,  metabolism
Disease Models, Animal
Gastrointestinal Neoplasms / etiology,  metabolism,  prevention & control*
Gene Expression
Inflammation Mediators / metabolism
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Proteins / antagonists & inhibitors*,  genetics,  metabolism
STAT3 Transcription Factor / genetics,  metabolism
Signal Transduction
Sirolimus / analogs & derivatives,  pharmacology
Reg. No./Substance:
0/Inflammation Mediators; 0/Proteins; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 0/Stat3 protein, mouse; 0/mechanistic target of rapamycin complex 1; 133483-10-0/Cytokine Receptor gp130; 159351-69-6/everolimus; 53123-88-9/Sirolimus

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