Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcΔ716 mice
Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcΔ716 mice
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DOI：
10.1073/pnas.0800041105
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发表时间：
2008-09-09
影响因子：
11.1
通讯作者：
Taketo, Makoto M.
中科院分区：
文献类型：
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作者：
Fujishita, Teruaki;Aoki, Koji;Taketo, Makoto M.
哺乳动物雷帕霉素靶蛋白（mTOR）是一种丝氨酸/苏氨酸激酶，通过mTOR复合物1（mTORC 1）调节细胞生长，其激活与许多人类癌症有关。然而，mTORC 1在胃肠道肿瘤中的地位尚未得到彻底的表征。我们已经发现，mTORC 1通路被激活的APC（德尔塔716）杂合突变小鼠，人类家族性腺瘤性息肉病模型的肠息肉中的mTOR蛋白的表达增加。用RAD 001（依维莫司）治疗8周抑制了这些息肉中的mTORC 1活性，并抑制了腺瘤细胞的增殖以及肿瘤血管生成，这不仅显着减少了息肉的数量，而且还减少了它们的大小。结肠癌细胞系中的β-连环蛋白敲低降低了mTOR水平，从而抑制了mTORC 1信号传导。这些结果表明，Wnt信号通过增加mTOR水平而促进mTORC 1的激活，并且该激活在肠息肉的形成和生长中起重要作用。事实上，长期的RAD 001治疗显著降低了Apc（Delta 716）小鼠的死亡率。因此，我们提出mTOR抑制剂可有效用于治疗和预防具有Wnt信号传导激活的结肠腺瘤和癌症。
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth via mTOR complex 1 (mTORC1), whose activation has been implicated in many human cancers. However, mTORC1's status in gastrointestinal tumors has not been characterized thoroughly. We have found that the mTORC1 pathway is activated with increased expression of the mTOR protein in intestinal polyps of the Apc(Delta 716) heterozygous mutant mouse, a model for human familial adenomatous polyposis. An 8-week treatment with RAD001 (everolimus) suppressed the mTORC1 activity in these polyps and inhibited proliferation of the adenoma cells as well as tumor angiogenesis, which significantly reduced not only the number of polyps but also their size. beta-Catenin knockdown in the colon cancer cell lines reduced the mTOR level and thereby inhibited the mTORC1 signaling. These results suggest that the Wnt signaling contributes to mTORC1 activation through the increased level of mTOR and that the activation plays important roles in the intestinal polyp formation and growth. indeed, long-term RAD001 treatment significantly reduced mortality of the Apc(Delta 716) mice. Thus, we propose that the mTOR inhibitors may be efficacious for therapy and prevention of colonic adenomas and cancers with Wnt signaling activation.