ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases.
ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases.
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DOI：
10.1126/scisignal.aac4374
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发表时间：
2016-02-16
影响因子：
7.3
通讯作者：
El-Deiry WS
中科院分区：
文献类型：
--
作者：
Kline CL;Van den Heuvel AP;Allen JE;Prabhu VV;Dicker DT;El-Deiry WS
ONC201(又称TIC10)是一种小分子，它通过促凋亡蛋白TRAIL失活促进细胞增殖和存活的蛋白激酶AKT和ERK，诱导细胞死亡。ONC201目前正处于各种恶性肿瘤的早期临床测试阶段。在这里，我们通过基因表达和蛋白质分析发现，ONC201通过涉及转录因子ATF4、反式激活因子CHOP和TRAIL受体DR5的综合应激反应(ISR)引发TRAIL丰度增加和细胞死亡。在对ONC201耐药的癌细胞中，ATF4不被激活，在对ONC201敏感的细胞中，ATF4或CHOP的敲除部分消除了ONC201诱导的细胞毒作用，并降低了ONC201刺激的DR5丰度的增加。ONC201激活ATF4需要HrI和PKR两种激动酶，它们磷酸化并激活翻译起始因子eIF2α。ONC201迅速引发细胞周期停滞，这与细胞周期蛋白D1的丰度降低、激酶复合体mTORC1的活性降低以及视网膜母细胞瘤(Rb)蛋白的去磷酸化有关。X连锁凋亡抑制蛋白(XIAP)的丰度与ONC201诱导的细胞凋亡程度呈负相关。ONC201的这些作用与癌细胞是否具有正常或突变的P53无关。因此，ONC201通过ISR途径协同诱导TRAIL诱导细胞死亡。
ONC201 (also called TIC10) is a small molecule that inactivates the cell proliferation- and cell survival-promoting kinases AKT and ERK and induces cell death through the pro-apoptotic protein TRAIL. ONC201 is currently in early phase clinical testing for various malignancies. Here, we found through gene expression and protein analyses that ONC201 triggered an increase in TRAIL abundance and cell death through an integrated stress response (ISR) involving the transcription factor ATF4, the transactivator CHOP, and the TRAIL receptor DR5. ATF4 was not activated in ONC201-resistant cancer cells, and in ONC201-sensitive cells, knockdown of ATF4 or CHOP partially abrogated ONC201-induced cytotoxicity and diminished the ONC201-stimulated increase in DR5 abundance. The activation of ATF4 in response to ONC201 required the kinases HRI and PKR, which phosphorylate and activate the translation initiation factor eIF2α. ONC201 rapidly triggered cell cycle arrest, which was associated with decreased abundance of cyclin D1, decreased activity of the kinase complex mTORC1, and dephosphorylation of the retinoblastoma (Rb) protein. The abundance of X-linked inhibitor of apoptosis protein (XIAP) negatively correlated with the extent of apoptosis in response to ONC201. These effects of ONC201 were independent of whether cancer cells had normal or mutant p53. Thus, ONC201 induces cell death through the coordinated induction of TRAIL by an ISR pathway.