mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice

Thiem, S; Pierce, TP; Palmieri, M; Putoczki, TL; Buchert, M; Preaudet, A; Farid, RO; Love, C; Catimel, B; Lei, ZD; Rozen, S; Gopalakrishnan, V; Schaper, F; Hallek, M; Boussioutas, A; Tan, P; Jarnicki, A; Ernst, M

Author(s): Thiem, S; Pierce, TP; Palmieri, M; Putoczki, TL; Buchert, M; Preaudet, A; Farid, RO; Love, C; Catimel, B; Lei, ZD; Rozen, S; Gopalakrishnan, V; Schaper, F; Hallek, M; Boussioutas, A; Tan, P; Jarnicki, A; Ernst, M;
Details: Publication Year 2013-02,Volume 123,Issue #2,Page 767-781
Journal Title: JOURNAL OF CLINICAL INVESTIGATION
Publication Type: Journal Article
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.
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Keywords: COLITIS-ASSOCIATED CANCER; GP130 MUTANT MICE; GASTRIC-CANCER; COLORECTAL-CANCER; MAMMALIAN TARGET; PHOSPHATIDYLINOSITOL 3-KINASE; THERAPEUTIC TARGET; TUMOR ANGIOGENESIS; LINKS INFLAMMATION; SOMATIC MUTATIONS
Research Division(s): Cell Signalling And Cell Death
Link To PubMed Central Version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561832/
Publisher's Version: https://doi.org/10.1172/JCI65086

Creation Date: 2013-02-01 12:00:00