novelchopactivatorlgh00168inducesnecroptosisina549humanlungcancercellsviarosmediatederstressandnfkbinhibition
文献类型：期刊论文
| 作者 | Ma Yiming1; Peng Yanmin1; Zhu Qionghua2; Gao Anhui1; Chao Bo3; He Qiaojun2; Li Jia1 ; Hu Youhong1; Zhou Yubo1
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| 刊名 | actapharmacologicasinica
 |
| 出版日期 | 2016 |
| 卷号 | 37期号:10页码:1381 |
| 关键词 | CHOP LGH00168 ER stress NF-kB necroptosis RIP1 ROS non-small cell lung cancer A549 cells cancer xenograft mice |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2016.61 |
| 英文摘要 | Aim: C/EBP homologous protein (CHOP) is a transcription factor that is activated at multiple levels during ER stress and plays an important role in ER stress-induced apoptosis. In this study we identified a novel CHOP activator, and further investigated its potential to be a therapeutic agent for human lung cancer. Methods: HEK293-CHOP-luc reporter cells were used in high-throughput screening (HTS) to identify CHOP activators. The cytotoxicity against cancer cells in vitro was measured with MTT assay. The anticancer effects were further examined in A549 human non-small cell lung cancer xenograft mice. The mechanisms underlying CHOP activation were analyzed using luciferase assays, and the anticancer mechanisms were elucidated in A549 cells. Results: From chemical libraries of 50000 compounds, LGH00168 was identified as a CHOP activator, which showed cytotoxic activities against a panel of 9 cancer cell lines with an average IC_(50) value of 3.26 μmol/L. Moreover, administration of LGH00168 significantly suppressed tumor growth in A549 xenograft bearing mice. LGH00168 activated CHOP promoter via AARE1 and AP1 elements, increased DR5 expression, decreased Bcl-2 expression, and inhibited the NF-kB pathway. Treatment of A549 cells with LGH00168 (10 μmol/L) did not induce apoptosis, but lead to RIPl-dependent necroptosis, accompanied by cell swelling, plasma membrane rupture, lysosomal membrane permeabilization,MMP collapse and caspase 8 inhibition. Furthermore, LGH00168 (10 and 20 μmol/L) dose-dependently induced mito-ROS production in A549 cells, which was reversed by the ROS scavenger N-acetyl-L-cysteine (NAC, 10 mmol/L). Moreover, NAC significantly diminished LGH00168-induced CHOP activation, NF-kB inhibition and necroptosis in A549 cells. Conclusion: LGH00168 is a CHOP activator that inhibits A549 cell growth in vitro and lung tumor growth in vivo. |
| 语种 | 英语 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/285296]  |
| 专题 | 中国科学院上海药物研究所 |
| 作者单位 | 1.中国科学院上海药物研究所 2.Department of Pharmacology and Toxicology, College of Pharmaceutical Sciences,Zhejiang University 3.北京大学 |
| 推荐引用方式 GB/T 7714 | Ma Yiming,Peng Yanmin,Zhu Qionghua,et al. novelchopactivatorlgh00168inducesnecroptosisina549humanlungcancercellsviarosmediatederstressandnfkbinhibition[J]. actapharmacologicasinica,2016,37(10):1381. |
| APA | Ma Yiming.,Peng Yanmin.,Zhu Qionghua.,Gao Anhui.,Chao Bo.,...&Zhou Yubo.(2016).novelchopactivatorlgh00168inducesnecroptosisina549humanlungcancercellsviarosmediatederstressandnfkbinhibition.actapharmacologicasinica,37(10),1381. |
| MLA | Ma Yiming,et al."novelchopactivatorlgh00168inducesnecroptosisina549humanlungcancercellsviarosmediatederstressandnfkbinhibition".actapharmacologicasinica 37.10(2016):1381. |
入库方式： OAI收割
来源：上海药物研究所
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