1. mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice.
- Author
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Thiem S, Pierce TP, Palmieri M, Putoczki TL, Buchert M, Preaudet A, Farid RO, Love C, Catimel B, Lei Z, Rozen S, Gopalakrishnan V, Schaper F, Hallek M, Boussioutas A, Tan P, Jarnicki A, and Ernst M
- Subjects
- Animals, Cytokine Receptor gp130 genetics, Cytokine Receptor gp130 metabolism, Disease Models, Animal, Everolimus, Female, Gastrointestinal Neoplasms etiology, Gastrointestinal Neoplasms metabolism, Gene Expression, Humans, Inflammation Mediators metabolism, Male, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Multiprotein Complexes, Proteins genetics, Proteins metabolism, STAT3 Transcription Factor genetics, STAT3 Transcription Factor metabolism, Signal Transduction, Sirolimus analogs & derivatives, Sirolimus pharmacology, TOR Serine-Threonine Kinases, Gastrointestinal Neoplasms prevention & control, Proteins antagonists & inhibitors
- 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. 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.
- Published
- 2013
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