mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice

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.

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner

“…Therefore, reduction of REDD1 by IL-6 could contribute to the development of proliferative diseases in inflammatory conditions. In line with this hypothesis activation of mTOR is required for inflammation-associated development of gastrointestinal tumors [43]. However, also increased REDD1 expression has been linked to the development of ovarian [50] and prostate cancer by desensitizing cells to apoptotic stimuli [51].…”

“…mTOR is essential for IL-6-induced tumor growth [43], it mediates IL-6-induced hepatic insulin resistance [44] and contributes to the development of non-alcoholic fatty liver disease in inflammatory conditions [45]. Interestingly, mTOR activity triggers shedding of the IL-6Rα, thereby increasing pro-inflammatory IL-6 trans-signalling hence building a positive feedback loop [46].…”

Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models

“…Aberrant activation of mTORC1 has been tightly linked to colorectal polyposis and tumors in both humans and mice (41)(42)(43). Inhibition of mTORC1 activity through genetic or pharmaceutical approaches has been demonstrated to be efficient at reducing cancer progression (22,44), suggesting a tumorigenic role of mTORC1 signaling in the intestine.…”

Signal Transducer and Activator of Transcription 3 - A Promising Target in Colitis-Associated Cancer

“…The crosstalk between STAT3 and mTOR is vital in several physiological and malignant conditions (Riemenschneider et al, 2006;Zhou et al, 2007;Kim et al, 2008;Wang et al, 2008;Thiem et al, 2013). STAT3 and mTOR are highly activated in epithelial and tumor cells in the inflamed colon.…”