Altering chemosensitivity by modulating translation elongation.
Altering chemosensitivity by modulating translation elongation.
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DOI：
10.1371/journal.pone.0005428
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Pelletier J
中科院分区：
文献类型：
--
作者：
Robert F;Carrier M;Rawe S;Chen S;Lowe S;Pelletier J
翻译过程发生在许多信号通路和发育过程下游的连接点。在E-μ-Myc小鼠中模拟PTEN/AKT/mTOR通路的激活是研究体内肿瘤基因型/化疗敏感性关系的有价值的工具。在这个模型中，用核糖体招募步骤的抑制剂西维斯特罗阻断翻译启动，可以调节肿瘤对标准化疗效果的敏感性。然而，翻译延长的抑制剂已经作为潜在的抗癌治疗药物在体外进行了测试，但还没有在基因明确的小鼠肿瘤模型中进行广泛的测试，或者与标准护理试剂的潜在协同作用。在这里，我们选择了四种结构不同的翻译延长化学抑制剂：高三尖杉酯碱、布鲁氏菌素、白粉菌素B和放线菌素，并测试了它们改变含有Pten、Tsc2、Bcl2或eif4E病变的Eμ-myc淋巴瘤的化疗耐药性的能力。我们发现，在某些遗传环境中，翻译延长抑制剂能够通过恢复肿瘤细胞的凋亡程序而与阿霉素协同作用。我们将这种影响归因于半衰期短的促癌或促生存蛋白水平的降低，如Mcl-1、细胞周期蛋白D1或c-Myc。使用体外培养的淋巴瘤细胞，我们复制了在小鼠中观察到的化疗和延长抑制之间的协同作用，并表明这种协同作用可以通过用蛋白酶体抑制剂阻止蛋白质降解来逆转。我们的结果表明，通过抑制短命促生存因子的合成来耗尽它们，可以在携带PTEN/AKT/mTOR通路突变的肿瘤中实现治疗反应。
The process of translation occurs at a nexus point downstream of a number of signal pathways and developmental processes. Modeling activation of the PTEN/AKT/mTOR pathway in the Eμ-Myc mouse is a valuable tool to study tumor genotype/chemosensitivity relationships in vivo. In this model, blocking translation initiation with silvestrol, an inhibitor of the ribosome recruitment step has been showed to modulate the sensitivity of the tumors to the effect of standard chemotherapy. However, inhibitors of translation elongation have been tested as potential anti-cancer therapeutic agents in vitro, but have not been extensively tested in genetically well-defined mouse tumor models or for potential synergy with standard of care agents. Here, we chose four structurally different chemical inhibitors of translation elongation: homoharringtonine, bruceantin, didemnin B and cycloheximide, and tested their ability to alter the chemoresistance of Eμ-myc lymphomas harbouring lesions in Pten, Tsc2, Bcl-2, or eIF4E. We show that in some genetic settings, translation elongation inhibitors are able to synergize with doxorubicin by reinstating an apoptotic program in tumor cells. We attribute this effect to a reduction in levels of pro-oncogenic or pro-survival proteins having short half-lives, like Mcl-1, cyclin D1 or c-Myc. Using lymphomas cells grown ex vivo we reproduced the synergy observed in mice between chemotherapy and elongation inhibition and show that this is reversed by blocking protein degradation with a proteasome inhibitor. Our results indicate that depleting short-lived pro-survival factors by inhibiting their synthesis could achieve a therapeutic response in tumors harboring PTEN/AKT/mTOR pathway mutations.
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DOI：
10.1124/jpet.106.110007
发表时间：
2006-12-01
影响因子：
3.5
作者：
Bai, Jingxiang;Cederbaum, Arthur I.
通讯作者：
Cederbaum, Arthur I.
影响因子：
2.1
作者：
Beasley, VR;Bruno, SJ;Levengood, JM
通讯作者：
Levengood, JM
DOI：
10.1111/j.1432-1033.1977.tb11256.x
发表时间：
1977-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
FRESNO, M;JIMENEZ, A;VAZQUEZ, D
通讯作者：
VAZQUEZ, D
影响因子：
3.6
作者：
Budihardjo, II;Boerner, SA;Kaufmann, SH
通讯作者：
Kaufmann, SH
影响因子：
64.8
作者：
LAZARISKARATZAS, A;MONTINE, KS;SONENBERG, N
通讯作者：
SONENBERG, N