Rapamycin-Induced Feedback Activation of eIF4E-EIF4A Dependent mRNA Translation in Pancreatic Cancer.
Rapamycin-Induced Feedback Activation of eIF4E-EIF4A Dependent mRNA Translation in Pancreatic Cancer.
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胰腺癌是一种侵袭性癌症，由于缺乏检测、有效治疗和治疗耐药性的发展，存活率很低。迫切需要新的治疗方法和治疗耐药性的机制细节。在这项研究中，我们探讨了抑制蛋白质合成的效果及其在诱导可能影响治疗反应的反馈机制中的作用。我们发现，雷帕霉素（西罗莫司）治疗抑制癌细胞生长所需的蛋白质的合成。有趣的是，雷帕霉素处理诱导了导致关键激酶重新激活的蛋白质的合成，这限制了雷帕霉素的抗肿瘤作用。我们进一步表明，雷帕霉素与小分子抑制剂CR-1-31-B的组合增加了雷帕霉素的功效。我们的研究建立了由雷帕霉素和新的治疗组合诱导的反馈机制，可以进一步开发为胰腺癌的治疗方法。胰腺癌细胞适应分子机制来激活蛋白质合成以支持肿瘤生长。这项研究报告了mTOR抑制剂雷帕霉素对mRNA翻译的特异性和全基因组效应。在缺乏4 EBP 1表达的胰腺癌细胞中使用核糖体足迹法，我们建立了mTOR-S6依赖性mRNA翻译的作用。雷帕霉素抑制包括p70-S6 K和参与细胞周期和癌细胞生长的蛋白质在内的mRNA子集的翻译。此外，我们确定了mTOR抑制后激活的翻译程序。有趣的是，雷帕霉素处理导致参与mTOR信号传导的激酶如p90-RSK 1的翻译激活。我们进一步表明，磷酸-AKT 1和磷酸-eIF 4 E上调后，mTOR抑制表明反馈激活雷帕霉素的翻译。接下来，通过使用特异性eIF 4A抑制剂与雷帕霉素组合靶向eIF 4 E和eIF 4A依赖性翻译显示出胰腺癌细胞中的显著生长抑制。简而言之，我们建立了mTOR-S6对缺乏4 EBP 1的细胞中翻译的特异性作用，并表明mTOR抑制通过AKT-RSK 1-eIF 4 E信号导致翻译的反馈激活。因此，靶向mTOR的翻译下游提供了胰腺癌中更有效的治疗策略。
Pancreatic cancer is aggressive cancer with a low survival rate due to the lack of detection, effective treatment, and development of therapeutic resistance. New treatments and mechanistic details of therapeutic resistance are urgently needed. In this study, we explored the effect of inhibiting protein synthesis and its role in inducing feedback mechanisms that may impact the therapeutic response. We show that Rapamycin (sirolimus) treatment inhibited the synthesis of proteins required for cancer cell growth. Interestingly, rapamycin treatment induced the synthesis of proteins that lead to reactivation of the key kinases, and this limited the anti-tumor effect of rapamycin. We further show that the combination of rapamycin with the small molecule inhibitor CR-1-31-B increases the efficacy of rapamycin. Our study establishes the feedback mechanism induced by rapamycin and new therapeutic combinations that can be further developed as therapeutics for pancreatic cancer. Pancreatic cancer cells adapt molecular mechanisms to activate the protein synthesis to support tumor growth. This study reports the mTOR inhibitor rapamycin’s specific and genome-wide effect on mRNA translation. Using ribosome footprinting in pancreatic cancer cells that lack the expression of 4EBP1, we establish the effect of mTOR-S6-dependent mRNAs translation. Rapamycin inhibits the translation of a subset of mRNAs including p70-S6K and proteins involved in the cell cycle and cancer cell growth. In addition, we identify translation programs that are activated following mTOR inhibition. Interestingly, rapamycin treatment results in the translational activation of kinases that are involved in mTOR signaling such as p90-RSK1. We further show that phospho-AKT1 and phospho-eIF4E are upregulated following mTOR inhibition suggesting a feedback activation of translation by rapamycin. Next, targeting eIF4E and eIF4A-dependent translation by using specific eIF4A inhibitors in combination with rapamycin shows significant growth inhibition in pancreatic cancer cells. In short, we establish the specific effect of mTOR-S6 on translation in cells lacking 4EBP1 and show that mTOR inhibition leads to feedback activation of translation via AKT-RSK1-eIF4E signals. Therefore, targeting translation downstream of mTOR presents a more efficient therapeutic strategy in pancreatic cancer.
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影响因子：
8
作者：
Martineau, Y.;Azar, R.;Pyronnet, S.
通讯作者：
Pyronnet, S.
DOI：
10.1038/nrc3106
发表时间：
2011-10-13
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.5
作者：
Mieulet, Virginie;Roceri, Mila;Pende, Mario
通讯作者：
Pende, Mario
影响因子：
64.8
作者：
Hsieh, Andrew C.;Liu, Yi;Edlind, Merritt P.;Ingolia, Nicholas T.;Janes, Matthew R.;Sher, Annie;Shi, Evan Y.;Stumpf, Craig R.;Christensen, Carly;Bonham, Michael J.;Wang, Shunyou;Ren, Pingda;Martin, Michael;Jessen, Katti;Feldman, Morris E.;Weissman, Jonathan S.;Shokat, Kevan M.;Rommel, Christian;Ruggero, Davide
通讯作者：
Ruggero, Davide
影响因子：
3.9
作者：
Siddiqui N;Sonenberg N
通讯作者：
Sonenberg N