Role of Dopamine Receptors in the Anticancer Activity of ONC201.
Role of Dopamine Receptors in the Anticancer Activity of ONC201.
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DOI：
10.1016/j.neo.2017.10.002
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
El-Deiry WS
中科院分区：
文献类型：
--
作者：
Kline CLB;Ralff MD;Lulla AR;Wagner JM;Abbosh PH;Dicker DT;Allen JE;El-Deiry WS
ONC201/TIC10是一种首创的肿瘤坏死因子相关凋亡诱导配体（TRAIL）小分子诱导剂，可引起综合应激反应的早期激活。其在体外有良好的安全性以及广谱疗效，这已在针对多种晚期恶性肿瘤的I/II期试验中得到证实。结合试验和报告基因检测表明，ONC201是多巴胺D2样受体（特别是DRD2和DRD3）的选择性拮抗剂。我们假设ONC201与DRD2的相互作用在ONC201的抗癌作用中起一定作用。通过cBioportal和定量逆转录聚合酶链反应分析，我们证实DRD2以细胞类型特异性的方式在不同癌细胞类型中表达。另一方面，通常检测不到DRD3。在DRD2水平较低的细胞中过表达DRD2会增加ONC201诱导的PARP裂解，在此之前会出现并且与ONC201诱导的CHOP mRNA表达增加相关。另一方面，在三种癌细胞系中使用CRISPR/Cas9敲除DRD2并不足以消除ONC201的抗癌作用。尽管在测试的癌细胞类型中ONC201的抗癌活性不依赖于DRD2的表达，但我们评估了阻断DRD2的细胞毒性潜力。在HCT116细胞中瞬时敲低DRD2会激活综合应激反应并减少细胞数量。对DRD2的药理拮抗作用显著降低细胞活力。因此，我们在本研究中证明，破坏多巴胺受体的表达和活性可产生细胞毒性作用，这可能至少部分是由于综合应激反应的激活。另一方面，ONC201的抗癌活性超出了其拮抗DRD2的能力，可能是由于ONC201能够激活其他独立于DRD2的通路。然而，通过小干扰RNA（siRNA）阻断多巴胺D1样受体DRD5或使用药理拮抗剂可促进ONC201诱导的抗癌活性。
ONC201/TIC10 is a first-in-class small molecule inducer of TRAIL that causes early activation of the integrated stress response. Its promising safety profile and broad-spectrum efficacy in vitro have been confirmed in Phase I/II trials in several advanced malignancies. Binding and reporter assays have shown that ONC201 is a selective antagonist of the dopamine D2-like receptors, specifically, DRD2 and DRD3. We hypothesized that ONC201’s interaction with DRD2 plays a role in ONC201’s anticancer effects. Using cBioportal and quantitative reverse-transcription polymerase chain reaction analyses, we confirmed that DRD2 is expressed in different cancer cell types in a cell type–specific manner. On the other hand, DRD3 was generally not detectable. Overexpressing DRD2 in cells with low DRD2 levels increased ONC201-induced PARP cleavage, which was preceded and correlated with an increase in ONC201-induced CHOP mRNA expression. On the other hand, knocking out DRD2 using CRISPR/Cas9 in three cancer cell lines was not sufficient to abrogate ONC201’s anticancer effects. Although ONC201’s anticancer activity was not dependent on DRD2 expression in the cancer cell types tested, we assessed the cytotoxic potential of DRD2 blockade. Transient DRD2 knockdown in HCT116 cells activated the integrated stress response and reduced cell number. Pharmacological antagonism of DRD2 significantly reduced cell viability. Thus, we demonstrate in this study that disrupting dopamine receptor expression and activity can have cytotoxic effects that may at least be in part due to the activation of the integrated stress response. On the other hand, ONC201’s anticancer activity goes beyond its ability to antagonize DRD2, potentially due to ONC201’s ability to activate other pathways that are independent of DRD2. Nevertheless, blocking the dopamine D1-like receptor DRD5 via siRNA or the use of a pharmacological antagonist promoted ONC201-induced anticancer activity.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
29.4
作者：
Jandaghi, Pouria;Najafabadi, Hamed S.;Hoheisel, Joerg D.
通讯作者：
Hoheisel, Joerg D.
影响因子：
3.7
作者：
Basu, S;Dasgupta, PS
通讯作者：
Dasgupta, PS
ONC201 通过 TRAIL 依赖性和 TRAIL 独立机制在三阴性和非三阴性乳腺癌中显示出抗肿瘤作用。
影响因子：
5.7
作者：
Ralff MD;Kline CLB;Küçükkase OC;Wagner J;Lim B;Dicker DT;Prabhu VV;Oster W;El-Deiry WS
通讯作者：
El-Deiry WS
影响因子：
14.9
作者：
Brinkman EK;Chen T;Amendola M;van Steensel B
通讯作者：
van Steensel B