西亚试剂：mTORC怎样维持肿瘤生长

 mTORC1复合物(见于所有真核细胞中的一种蛋白激酶复合物)已被发现与肿瘤发生有关，因为它已知能刺激蛋白翻译。mTORC1下游的主要效应子通道被认为是4EBP1，后者促进翻译的启动。

现在，William Faller等人发现，在小鼠小肠中，mTORC1活性并不是正常动态平衡所需的，但却是由APC肿瘤抑制因子基因突变触发的小肠肿瘤形成所需的。

作者发现，通过伸长因子eEF2在S6激酶下游使翻译伸长量(translational elongation)增加是对缺失APC的细胞增殖的一个要求，但不是对正常细胞的增殖的一个要求。这表明，翻译伸长(而不是翻译启动)在活体中是癌细胞增殖的限制因素。

这些发现提出一个可能性：以TORC1信号作用为目标，对于防止高风险患者罹患结肠直肠癌也许会有好处。

原文链接：mTORC1-mediated translational elongation limits intestinal tumour initiation and growth

Inactivation of APC is a strongly predisposing event in the development of colorectal cancer1, 2, prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth3, 4, 5, and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1–S6K–eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer.

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