Cap-dependent mRNA translation and the ubiquitin-proteasome system cooperate to promote ERBB2-dependent esophageal cancer phenotype.
Cap-dependent mRNA translation and the ubiquitin-proteasome system cooperate to promote ERBB2-dependent esophageal cancer phenotype.
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DOI：
10.1038/cgt.2012.39
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发表时间：
2012-09
影响因子：
6.4
通讯作者：
中科院分区：
文献类型：
--
作者：
蛋白质组组成的病理性转录后控制是恶性肿瘤的中心特征。这一途径中的两个步骤，eIF 4F驱动的帽依赖性mRNA翻译和泛素-蛋白酶体系统（UPS），在大多数（如果不是所有的话）癌症中被解除管制。我们检验了一个假设，即eIF 4F在人食管腺癌（EAC）中异常激活，需要蛋白质周转和蛋白水解速率升高，从而激活UPS的促肿瘤功能。在这里，我们发现80%的肿瘤和细胞系具有扩增的ERBB 2显示异常激活的eIF 4F。在ERBB 2扩增的EAC细胞中，用eIF 4F阻遏物4 E-BP 1的组成型活性形式直接遗传靶向eIF 4F，减少了集落形成和增殖，并触发了凋亡。相比之下，雷帕霉素抑制m-TOR-激酶对4 E-BP 1的活性仅适度抑制eIF 4F驱动的帽依赖性翻译和EAC恶性表型;并促进其他癌症途径的反馈激活。我们的数据表明，与2种FDA批准的药物，m-TOR抑制剂雷帕霉素和蛋白酶体抑制剂硼替佐米的共同治疗，导致强烈的协同生长抑制作用。此外，直接靶向eIF 4F与组成型活性4 E-BP 1在与硼替佐米的协作中比雷帕霉素显著更有效。这些数据支持以下假设：维持ERBB 2介导的EAC恶性表型需要eIF 4F驱动的蛋白质合成和蛋白酶体介导的蛋白质降解之间的微调平衡。总之，我们的研究支持开发直接靶向eIF 4F的药物作为最有效的策略;并为m-TOR抑制剂和硼替佐米联合治疗EAC的临床评价提供了明确的理论基础。
Pathological post-transcriptional control of the proteome composition is a central feature of malignancy. Two steps in this pathway, eIF4F-driven cap-dependent mRNA translation and the ubiquitin-proteasome system (UPS), are deregulated in most if not all cancers. We tested a hypothesis that eIF4F is aberrantly activated in human esophageal adenocarcinoma (EAC) and requires elevated rates of protein turnover and proteolysis and thereby activated UPS for its pro-neoplastic function. Here, we show that 80% of tumors and cell lines featuring amplified ERBB2 display an aberrantly activated eIF4F. Direct genetic targeting of the eIF4F in ERBB2-amplified EAC cells with a constitutively active form of the eIF4F repressor 4E-BP1 decreased colony formation and proliferation and triggered apoptosis. In contrast, suppression of m-TOR-kinase activity towards 4E-BP1with rapamycin only modestly inhibited eIF4F-driven cap-dependent translation and EAC malignant phenotype; and promoted feedback activation of other cancer pathways. Our data show that co-treatment with 2 FDA-approved agents, the m-TOR inhibitor rapamycin and the proteasome inhibitor bortezomib, leads to strong synergistic growth-inhibitory effects. Moreover, direct targeting of eIF4F with constitutively active 4E-BP1 is significantly more potent in collaboration with bortezomib than rapamycin. These data support the hypothesis that a finely tuned balance between eIF4F-driven protein synthesis and proteasome-mediated protein degradation is required for the maintenance of ERBB2-mediated EAC malignant phenotype. Altogether, our study supports the development of pharmaceuticals to directly target eIF4F as most efficient strategy; and provides a clear rationale for the clinical evaluation of combination therapy with m-TOR inhibitors and bortezomib for EAC treatment.
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影响因子：
8.8
作者：
Coleman, L. J.;Peter, M. B.;Teall, T. J.;Brannan, R. A.;Hanby, A. M.;Honarpisheh, H.;Shaaban, A. M.;Smith, L.;Speirs, V.;Verghese, E. T.;McElwaine, J. N.;Hughes, T. A.
通讯作者：
Hughes, T. A.
影响因子：
5.3
作者：
Li, SN;Sonenberg, N;Bitterman, PB
通讯作者：
Bitterman, PB
DOI：
10.1158/1078-0432.ccr-10-0433
发表时间：
2010-10-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hsieh AC;Ruggero D
通讯作者：
Ruggero D
影响因子：
9
作者：
Li, BDL;McDonald, JC;De Benedetti, A
通讯作者：
De Benedetti, A
影响因子：
11.4
作者：
Beretta, L;Gingras, AC;Sonenberg, N
通讯作者：
Sonenberg, N