3-Deoxy-2 beta,16-dihydroxynagilactone E, a natural compound from Podocarpus nagi, preferentially inhibits JAK2/STAT3 signaling by allosterically interacting with the regulatory domain of JAK2 and induces apoptosis of cancer cells
文献类型：期刊论文
| 作者 | Shan, Hui2,4; Yao, Sheng1,3,4 ; Ye, Yang1,3,4; Yu, Qiang2,4
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2019-12-01 |
| 卷号 | 40期号:12页码:1578-1586 |
| 关键词 | JAK/STAT 3-deoxy-2 beta,16-dihydroxynagilactone E tyrosine kinase inhibitor allosteric inhibitor cancer |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-019-0254-4 |
| 通讯作者 | Yu, Qiang(qyu@sibs.ac.cn) |
| 英文摘要 | The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, especially the JAK2/STAT3 pathway, play vital roles in the development of many malignancies. Overactivation of STAT3 promotes cancer cell survival and proliferation. Therefore, the JAK2/STAT3-signaling pathway has been considered a promising target for cancer therapy. In this study, we identified a natural compound 3-deoxy-2 beta,16-dihydroxynagilactone E (B6) from the traditional Chinese medicinal plant Podocarpus nagi as a potent inhibitor of STAT3 signaling. B6 preferentially inhibited the phosphorylation of STAT3 by interacting with and inactivating JAK2, the main upstream kinase of STAT3. B6 dose-dependently inhibited IL-6-induced STAT3 signaling with an IC50 of 0.2 mu M. In contrast to other JAK2 inhibitors, B6 did not interact with the catalytic domain but instead with the FERM-SH2 domain of JAK2. This interaction was JAK-specific since B6 had little effect on other tyrosine kinases. Furthermore, B6 potently inhibited the growth and induced apoptosis of MDA-MB-231 and MDA-MB-468 breast cancer cells with overactivated STAT3. Taken together, our study uncovers a novel compound and a novel mechanism for the regulation of JAK2 and offers a new therapeutic approach for the treatment of cancers with overactivated JAK2/STAT3. |
| WOS关键词 | JANUS KINASE FAMILY ; ACTIVATION ; GROWTH ; STAT3 ; AZD1480 ; ROLES ; TRANSDUCER ; DISCOVERY ; PATHWAYS ; SURVIVAL |
| 资助项目 | National Natural Science Foundation of China[81673465] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000500546400008 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/282072]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Yu, Qiang |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Nat Prod Chem Dept, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Shan, Hui,Yao, Sheng,Ye, Yang,et al. 3-Deoxy-2 beta,16-dihydroxynagilactone E, a natural compound from Podocarpus nagi, preferentially inhibits JAK2/STAT3 signaling by allosterically interacting with the regulatory domain of JAK2 and induces apoptosis of cancer cells[J]. ACTA PHARMACOLOGICA SINICA,2019,40(12):1578-1586. |
| APA | Shan, Hui,Yao, Sheng,Ye, Yang,&Yu, Qiang.(2019).3-Deoxy-2 beta,16-dihydroxynagilactone E, a natural compound from Podocarpus nagi, preferentially inhibits JAK2/STAT3 signaling by allosterically interacting with the regulatory domain of JAK2 and induces apoptosis of cancer cells.ACTA PHARMACOLOGICA SINICA,40(12),1578-1586. |
| MLA | Shan, Hui,et al."3-Deoxy-2 beta,16-dihydroxynagilactone E, a natural compound from Podocarpus nagi, preferentially inhibits JAK2/STAT3 signaling by allosterically interacting with the regulatory domain of JAK2 and induces apoptosis of cancer cells".ACTA PHARMACOLOGICA SINICA 40.12(2019):1578-1586. |
入库方式： OAI收割
来源：上海药物研究所
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