Parthenolide Inhibits STAT3 Signaling by Covalently Targeting Janus Kinases
文献类型：期刊论文
| 作者 | Liu, Man1,5; Xiao, Chengqian2,4; Sun, Mingwei1,3; Tan, Minjia1,3 ; Hu, Lihong4; Yu, Qiang1,5
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| 刊名 | MOLECULES
 |
| 出版日期 | 2018-06 |
| 卷号 | 23期号:6 |
| 关键词 | parthenolide covalent inhibitor cell death JAK/STAT3 signaling |
| ISSN号 | 1420-3049 |
| DOI | 10.3390/molecules23060000 |
| 文献子类 | Article |
| 英文摘要 | Aberrant activations of the STAT3 (signal transducer and activator of transcription 3) signaling pathway are associated with cancer and inflammatory diseases. Three of the four Janus kinases, JAK1, JAK2, and Tyk2, are the major upstream kinases of STAT3 in responses to cytokine stimulations. Among them, JAK2 is the key kinase in the IL-6-induced STAT3 phosphorylation. Here we report the mechanisms of a natural compound parthenolide from the medicinal herb Feverfew in regulating the JAK/STAT3 signaling. We found that parthenolide was a potent inhibitor of JAKs. It covalently modified the Cys178, Cys243, Cys335, and Cys480 of JAK2 and suppressed its kinase activity. It also interacted with other JAKs in a similar fashion. The binding of parthenolide to JAKs was selective. It preferentially bound to the JAKs, but not to the abundant proteins, such as tubulin and actin. Parthenolide also induced reactive oxygen species (ROS), but the increased ROS did not seem to contribute to the inhibition of JAK/STAT3 signaling. Furthermore, parthenolide inhibited the IL-6-induced cancer cell migration and preferentially inhibited the growth of cancer cells that had constitutively activated STAT3. Our study suggests a novel strategy to inactivate JAKs and provides a promising anti-inflammation and anticancer drug candidate. |
| WOS关键词 | BREAST-CANCER CELLS ; NF-KAPPA-B ; JAK2 INHIBITOR ; OXIDATIVE STRESS ; MYELOPROLIFERATIVE DISORDERS ; POLYCYTHEMIA-VERA ; STRUCTURAL BASIS ; FERM DOMAIN ; ACTIVATION ; RECEPTOR |
| 资助项目 | National Natural Science Foundation of China[81673465] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000435875400239 |
| 出版者 | MDPI |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279720]  |
| 专题 | 化学蛋白质组学研究中心 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 药理学第一研究室 |
| 通讯作者 | Yu, Qiang |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 2.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Chem Prote Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 4.Nanjing Univ Chinese Med, Stake Key Lab Cultivat Base TCM Qual & Efficacy, Jiangsu Collaborat Innovat Ctr Chinese Med Resour, Jiangsu Key Lab Funct Subst Chinese Med,Sch Pharm, Nanjing 210023, Jiangsu, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Liu, Man,Xiao, Chengqian,Sun, Mingwei,et al. Parthenolide Inhibits STAT3 Signaling by Covalently Targeting Janus Kinases[J]. MOLECULES,2018,23(6). |
| APA | Liu, Man,Xiao, Chengqian,Sun, Mingwei,Tan, Minjia,Hu, Lihong,&Yu, Qiang.(2018).Parthenolide Inhibits STAT3 Signaling by Covalently Targeting Janus Kinases.MOLECULES,23(6). |
| MLA | Liu, Man,et al."Parthenolide Inhibits STAT3 Signaling by Covalently Targeting Janus Kinases".MOLECULES 23.6(2018). |
入库方式： OAI收割
来源：上海药物研究所
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