Induction of Activating Transcription Factor 3 Is Associated with Cisplatin Responsiveness in Non-Small Cell Lung Carcinoma Cells.
Induction of Activating Transcription Factor 3 Is Associated with Cisplatin Responsiveness in Non-Small Cell Lung Carcinoma Cells.
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DOI：
10.1016/j.neo.2016.07.004
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发表时间：
2016-09
期刊：
影响因子：
4.8
通讯作者：
Dimitroulakos, Jim
中科院分区：
文献类型：
--
作者：
Bar, Jair;Hasim, Mohamed S.;Baghai, Tabassom;Niknejad, Nima;Perkins, Theodore J.;Stewart, David J.;Sekhon, Harmanjatinder S.;Villeneuve, Patrick J.;Dimitroulakos, Jim
非小细胞肺癌（NSCLC）是癌症死亡的最常见原因，以铂为基础的联合化疗是最有效的治疗方法。总生存期的增加是适度的，突出了对新的治疗方法的需求，包括开发下一代铂类联合治疗方案。本研究的目的是确定铂诱导的细胞毒性的新调节剂作为潜在的治疗靶点，以进一步增强铂的细胞毒性。采用RNA-seq转录组分析比较两种亲本NSCLC细胞系Calu 6和H23与其顺铂耐药亚系Calu 6cisR 1和H23 cisR 1，在顺铂处理的亲本敏感细胞系而不是其耐药亚系中，以及在评估的6个肿瘤中的3个中，激活转录因子3（ATF 3）被稳健诱导，但在其相应的正常相邻肺组织中未被诱导（0/6）。顺铂诱导的JNK活化是这种ATF 3诱导的关键调节因子。有趣的是，在两个耐药亚系中，这种JNK诱导被废除，并且在这些细胞中活化的JNK构建体的表达增强顺铂诱导的细胞毒性和ATF 3诱导。采用FDA批准的药物化合物筛选来鉴定依赖于ATF 3基因表达的顺铂细胞毒性的增强剂。伏立诺他是一种组蛋白脱乙酰酶抑制剂，在该筛选中被鉴定，并且在亲本Calu 6和H23细胞系中以及重要的是在它们的抗性亚系中与顺铂显示出协同细胞毒性，这依赖于ATF 3表达。因此，我们已经确定了ATF 3作为顺铂细胞毒性的重要调节剂，并且ATF 3诱导剂与铂类药物组合是NSCLC的潜在新治疗方法。
Non–small cell lung carcinoma (NSCLC) is the most common cause of cancer deaths, with platin-based combination chemotherapy the most efficacious therapies. Gains in overall survival are modest, highlighting the need for novel therapeutic approaches including the development of next-generation platin combination regimens. The goal of this study was to identify novel regulators of platin-induced cytotoxicity as potential therapeutic targets to further enhance platin cytotoxicity. Employing RNA-seq transcriptome analysis comparing two parental NSCLC cell lines Calu6 and H23 to their cisplatin-resistant sublines, Calu6cisR1 and H23cisR1, activating transcription factor 3 (ATF3) was robustly induced in cisplatin-treated parental sensitive cell lines but not their resistant sublines, and in three of six tumors evaluated, but not in their corresponding normal adjacent lung tissue (0/6). Cisplatin-induced JNK activation was a key regulator of this ATF3 induction. Interestingly, in both resistant sublines, this JNK induction was abrogated, and the expression of an activated JNK construct in these cells enhanced both cisplatin-induced cytotoxicity and ATF3 induction. An FDA-approved drug compound screen was employed to identify enhancers of cisplatin cytotoxicity that were dependent on ATF3 gene expression. Vorinostat, a histone deacetylase inhibitor, was identified in this screen and demonstrated synergistic cytotoxicity with cisplatin in both the parental Calu6 and H23 cell lines and importantly in their resistant sublines as well that was dependent on ATF3 expression. Thus, we have identified ATF3 as an important regulator of cisplatin cytotoxicity and that ATF3 inducers in combination with platins are a potential novel therapeutic approach for NSCLC.
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影响因子：
3.5
作者：
Aisner, Dara L.;Marshall, Carrie B.
通讯作者：
Marshall, Carrie B.
影响因子：
2.8
作者：
Kroupis, C;Stathopoulou, A;Lianidou, ES
通讯作者：
Lianidou, ES
影响因子：
3
作者：
Manic, S.;Gatti, L.;Perego, P.
通讯作者：
Perego, P.
影响因子：
4.8
作者：
Kostenko, Sergiy;Johannessen, Mona;Moens, Ugo
通讯作者：
Moens, Ugo
DOI：
10.2174/1568011053765967
发表时间：
2005-05-05
期刊：
Current Medicinal Chemistry - Anti-Cancer Agents
影响因子：
--
作者：
Sedletska, Yuliya;Giraud-Panis, Marie-Josephe;Malinge, Jean-Marc
通讯作者：
Malinge, Jean-Marc