Novel CHOP activator LGH00168 induces necroptosis in A549 human lung cancer cells via ROS-mediated ER stress and NF-kappa B inhibition
文献类型：期刊论文
| 作者 | Ma, Yi-ming1; Peng, Yan-min1; Zhu, Qiong-hua3; Gao, An-hui1; Chao, Bo2; He, Qiao-jun3; Li, Jia1 ; Hu, You-hong1; Zhou, Yu-bo1
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2016-10 |
| 卷号 | 37期号:10页码:1381-1390 |
| ISSN号 | 1671-4083 |
| 关键词 | CHOP LGH00168 ER stress NF-kappa B necroptosis RIP1 ROS non-small cell lung cancer A549 cells cancer xenograft mice |
| DOI | 10.1038/aps.2016.61 |
| 文献子类 | Article |
| 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 50 000 compounds, LGH00168 was identified as a CHOP activator, which showed cytotoxic activities against a panel of 9 cancer cell lines with an average IC50 value of 3.26 mu mol/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-kappa B pathway. Treatment of A549 cells with LGH00168 (10 mu mol/L) did not induce apoptosis, but lead to RIP1-dependent necroptosis, accompanied by cell swelling, plasma membrane rupture, lysosomal membrane permeabilization, MMP collapse and caspase 8 inhibition. Furthermore, LGH00168 (10 and 20 mu mol/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-kappa B 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. |
| WOS关键词 | ENDOPLASMIC-RETICULUM STRESS ; INDUCED APOPTOSIS ; DEATH ; NECROSIS ; AUTOPHAGY ; THERAPY ; PATHWAY ; MITOCHONDRIA ; CHEMOTHERAPY ; CHAPERONE |
| 资助项目 | National Natural Science Foundation of China[81072667] ; National Natural Science Foundation of China[81473244] ; National Natural Science Foundation of China[91029716] ; State Key Laboratory of Natural and Biomimetic Drugs[K20130202] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:5820847 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| WOS记录号 | WOS:000385634300011 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275879]  |
| 专题 | 国家新药筛选中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Zhou, Yu-bo |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100871, Peoples R China; 3.Zhejiang Univ, Dept Pharmacol & Toxicol, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ma, Yi-ming,Peng, Yan-min,Zhu, Qiong-hua,et al. Novel CHOP activator LGH00168 induces necroptosis in A549 human lung cancer cells via ROS-mediated ER stress and NF-kappa B inhibition[J]. ACTA PHARMACOLOGICA SINICA,2016,37(10):1381-1390. |
| APA | Ma, Yi-ming.,Peng, Yan-min.,Zhu, Qiong-hua.,Gao, An-hui.,Chao, Bo.,...&Zhou, Yu-bo.(2016).Novel CHOP activator LGH00168 induces necroptosis in A549 human lung cancer cells via ROS-mediated ER stress and NF-kappa B inhibition.ACTA PHARMACOLOGICA SINICA,37(10),1381-1390. |
| MLA | Ma, Yi-ming,et al."Novel CHOP activator LGH00168 induces necroptosis in A549 human lung cancer cells via ROS-mediated ER stress and NF-kappa B inhibition".ACTA PHARMACOLOGICA SINICA 37.10(2016):1381-1390. |
入库方式： OAI收割
来源：上海药物研究所
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