mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice
mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice
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DOI：
10.1172/jci65086
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发表时间：
2013-02-01
影响因子：
15.9
通讯作者：
Ernst, Matthias
中科院分区：
文献类型：
--
作者：
Thiem, Stefan;Pierce, Thomas P.;Ernst, Matthias
胃肠道癌症通常与慢性炎症和IL-6家族细胞因子的过度分泌相关，其通过GP 130/JAK/STAT 3通路的持续激活促进肿瘤发生。虽然可以通过基因消融小鼠中的Stat 3来预防肿瘤进展，但这种转录因子仍然是一个具有挑战性的治疗靶点，缺乏临床批准的抑制剂。在这里，我们发现了在人类胃肠道型胃癌（IGCs）中mTOR复合物1（mTORC 1）与STAT 3的平行和过度激活。此外，在IGC的临床前小鼠模型中，GP 130配体给药同时激活mTORC 1/S6激酶和STAT 3信号传导。因此，我们研究了mTORC 1激活是否是炎症相关胃肠道肿瘤发生所必需的。引人注目的是，mTORC 1特异性抑制剂RAD 001有效地抑制了小鼠IGC和结肠炎相关结肠癌的发生和进展。RAD 001的治疗效果与减少的肿瘤血管形成和细胞增殖相关，但独立于STAT 3活性发生。我们分析了GP 130介导的mTORC 1在细胞和小鼠中活化的机制，并揭示了JAK和PI 3 K活性的需要，而不是GP 130酪氨酸磷酸化或STAT 3。我们的研究结果表明，GP 130依赖性激活的可药用PI 3 K/mTORC 1途径是炎症相关的胃肠道肿瘤发生所必需的。这些发现支持PI 3 K/mTORC 1抑制剂用于治疗相应的人类恶性肿瘤的临床应用。
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.