mTORC1-mediated translational elongation limits intestinal tumour initiation and growth.
mTORC1-mediated translational elongation limits intestinal tumour initiation and growth.
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DOI：
10.1038/nature13896
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发表时间：
2015-01-22
期刊：
影响因子：
64.8
通讯作者：
Sansom, Owen J.
中科院分区：
文献类型：
--
作者：
Faller, William J.;Jackson, Thomas J.;Knight, John R. P.;Ridgway, Rachel A.;Jamieson, Thomas;Karim, Saadia A.;Jones, Carolyn;Radulescu, Sorina;Huels, David J.;Myant, Kevin B.;Dudek, Kate M.;Casey, Helen A.;Scopelliti, Alessandro;Cordero, Julia B.;Vidal, Marcos;Pende, Mario;Ryazanov, Alexey G.;Sonenberg, Nahum;Meyuhas, Oded;Hall, Michael N.;Bushell, Martin;Willis, Anne E.;Sansom, Owen J.
APC的失活是结直肠癌发生发展中的一个强烈的易感事件，促使我们寻找丢失APC功能的细胞特有的脆弱性。已知通过mTOR通路的信号转导是上皮细胞增殖和肿瘤生长所必需的，目前的范式表明mTOR活性的一个关键功能是通过4EBP1的磷酸化上调翻译起始。该模型预测，mTOR抑制剂雷帕霉素不能有效抑制4EBP1，在限制APC缺陷皮损的癌症进展方面将无效。在这里，我们表明mTORC1活性是APC缺陷(但不是野生型)肠细胞增殖所绝对需要的，这揭示了一个意想不到的治疗干预机会。尽管APC缺陷细胞在蛋白质合成方面表现出预期的增加，但我们的研究表明，这是翻译延长，而不是启动，后者是限速成分。从机制上讲，mTORC1介导的eEF2激酶抑制是APC缺陷细胞增殖所必需的。重要的是，用雷帕霉素(可以通过mTORC1-S6K-eEF2K轴靶向eEF2)治疗已建立的APC缺陷性腺瘤会导致肿瘤细胞生长停滞和分化。综上所述，我们的数据表明，使用现有的临床批准的药物，如拉帕洛格，抑制翻译延长，将为结直肠癌高危患者提供明显的治疗益处。
Inactivation of APC is a strongly predisposing event in the development of colorectal cancer, prompting us to 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 growth and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1. This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1, would be ineffective in limiting cancer progression in APC deficient lesions. Here we show that 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 studies 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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DOI：
10.1158/1078-0432.ccr-09-1249
发表时间：
2009-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Gulhati P;Cai Q;Li J;Liu J;Rychahou PG;Qiu S;Lee EY;Silva SR;Bowen KA;Gao T;Evers BM
通讯作者：
Evers BM
影响因子：
9.9
作者：
通讯作者：
--
影响因子：
5.3
作者：
Banko, JL;Poulin, F;Klann, E
通讯作者：
Klann, E
影响因子：
8
作者：
Martineau, Y.;Azar, R.;Pyronnet, S.
通讯作者：
Pyronnet, S.
影响因子：
4.7
作者：
Bach, SP;Renehan, AG;Potten, CS
通讯作者：
Potten, CS