当前位置: X-MOL 学术Cancer Res. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Thermal proteome profiling identifies oxidative-dependent inhibition of the transcription of major oncogenes as a new therapeutic mechanism for select anticancer compounds.
Cancer Research ( IF 12.5 ) Pub Date : 2020-04-01 , DOI: 10.1158/0008-5472.can-19-2069
Sylvain Peuget 1 , Jiawei Zhu 1 , Gema Sanz 1 , Madhurendra Singh 1 , Massimiliano Gaetani 2, 3 , Xinsong Chen 4 , Yao Shi 1 , Amir Ata Saei 2 , Torkild Visnes 3, 4, 5 , Mikael S Lindström 2, 3 , Ali Rihani 1 , Lidia Moyano-Galceran 1 , Joseph W Carlson 4 , Elisabet Hjerpe 4 , Ulrika Joneborg 6 , Kaisa Lehti 1 , Johan Hartman 4 , Thomas Helleday 3, 4, 7 , Roman Zubarev 2, 3 , Galina Selivanova 1
Affiliation  

Identification of the molecular mechanism of action (MoA) of bioactive compounds is a crucial step for drug development but remains a challenging task despite recent advances in technology. In this study, we applied multidimensional proteomics, sensitivity correlation analysis and transcriptomics to identify a common mechanism of action for the anticancer compounds RITA, aminoflavone (AF) and oncrasin-1 (Onc-1). Global thermal proteome profiling (TPP) revealed that the three compounds target mRNA processing and transcription, thereby attacking a cancer vulnerability - transcriptional addiction. This led to the preferential loss of expression of oncogenes involved in PDGF-, EGFR-, VEGF-, Insulin/IGF/MAPKK-, FGF-, Hedgehog-, TGF-beta- and PI3K-signaling pathways. Increased reactive oxygen species (ROS) level in cancer cells was a prerequisite for targeting the mRNA transcription machinery, thus conferring cancer-selectivity to these compounds. Furthermore, DNA repair factors involved in homologous recombination were among the most prominently repressed proteins. In cancer patient samples, RITA, AF and Onc-1 sensitized to poly(ADP-ribose) polymerase inhibitors both in vitro and ex vivo. These findings might pave a way for new synthetic lethal combination therapies.

中文翻译:

热蛋白质组图谱鉴定主要致癌基因的转录的氧化依赖性抑制是选择抗癌化合物的新治疗机制。

鉴定生物活性化合物的分子作用机理(MoA)是药物开发的关键步骤,但尽管最近技术进步,但仍是一项艰巨的任务。在这项研究中,我们应用了多维蛋白质组学,敏感性相关分析和转录组学来确定抗癌化合物RITA,氨基黄酮(AF)和oncrasin-1(Onc-1)的共同作用机制。全球热蛋白质组分析(TPP)显示,这三种化合物靶向mRNA加工和转录,从而攻击了癌症易感性-转录成瘾。这导致涉及PDGF-,EGFR-,VEGF-,胰岛素/ IGF / MAPKK-,FGF-,刺猬,TGF-β和PI3K信号通路的致癌基因表达的优先丧失。癌细胞中增加的活性氧(ROS)水平是靶向mRNA转录机制的先决条件,因此赋予这些化合物以癌症选择性。此外,参与同源重组的DNA修复因子是最突出的抑制蛋白。在癌症患者样品中,RITA,AF和Onc-1在体外和离体时均对聚(ADP-核糖)聚合酶抑制剂敏感。这些发现可能为新的合成致死联合疗法铺平道路。
更新日期:2020-04-03
down
wechat
bug