Repression of cap-dependent translation attenuates the transformed phenotype in non-small cell lung cancer both in vitro and in vivo
Repression of cap-dependent translation attenuates the transformed phenotype in non-small cell lung cancer both in vitro and in vivo
复制标题
DOI：
10.1158/0008-5472.can-05-2879
复制
发表时间：
2006-04-15
期刊：
影响因子：
11.2
通讯作者：
Kratzke, RA
中科院分区：
文献类型：
--
作者：
Jacobson, BA;Alter, MD;Kratzke, RA
帽依赖蛋白合成装置的异常过度激活已在包括上皮性癌在内的多种实体肿瘤中得到证实，但其因果关系仅在乳腺癌中得到证实。在本报告中，我们试图确定在非小细胞肺癌（NSCLC）中，靶向破坏脱调控的帽依赖翻译是否会消除致瘤性并增强细胞死亡。用野生型4E-BP1 （RA-4E-BP1）或显性活性突变型4E-BPIA37/A46 （HA-TTAA）稳定转染NSCLC细胞系。转染的翻译抑制增强的NSCLC细胞在吉西他滨治疗后显示明显的细胞死亡。此外，在克隆效率实验中，转染的HA-TTAA和HA-4E-BP1（wt）蛋白抑制了生长。用HA-TTAA转导的非小细胞肺癌细胞在异种移植模型中也显示出降低的致瘤性。表达HA-TTAA的异种移植肿瘤明显小于对照肿瘤。这项工作表明，翻译机制的过度激活对于维持非小细胞肺癌的恶性表型是必要的，确定了用于激活翻译的分子策略，并支持直接靶向帽依赖翻译起始复合物的肺癌治疗的发展。
Aberrant hyperactivation of the cap-dependent protein synthesis apparatus has been documented in a wide range of solid tumors, including epithelial carcinomas, but causal linkage has only been established in breast carcinoma. In this report, we sought to determine if targeted disruption of deregulated cap-dependent translation abrogates tumorigenicity and enhances cell death in non-small cell lung cancer (NSCLC). NSCLC cell lines were stably transfected with either wild-type 4E-BP1 (RA-4E-BP1) or the dominant-active mutant 4E-BPIA37/A46 (HA-TTAA). Transfected NSCLC cells with enhanced translational repression showed pronounced cell death following treatment with gemcitabine. In addition, transfected HA-TTAA and HA-4E-BP1(wt) proteins suppressed growth in a cloning efficiency assay. NSCLC cells transduced with HA-TTAA also show decreased tumorigenicity in xenograft models. Xenograft tumors expressing HA-TTAA were significantly smaller than control tumors. This work shows that hyperactivation of the translational machinery is necessary for maintenance of the malignant phenotype in NSCLC, identifies the molecular strategy used to activate translation, and supports the development of lung cancer therapies that directly target the cap-dependent translation initiation complex.