3-Deoxy-2β,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

被引:24
作者
Shan, Hui [1 ,4 ]
Yao, Sheng [2 ,3 ,4 ]
Ye, Yang [2 ,3 ,4 ]
Yu, Qiang [1 ,4 ]
机构
[1] Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China
[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
[3] Chinese Acad Sci, Shanghai Inst Mat Med, Nat Prod Chem Dept, Shanghai 201203, Peoples R China
[4] Univ Chinese Acad Sci, Beijing 100049, Peoples R China
基金
中国国家自然科学基金;
关键词
JAK/STAT; 3-deoxy-2; beta; 16-dihydroxynagilactone E; tyrosine kinase inhibitor; allosteric inhibitor; cancer; JANUS KINASE FAMILY; ACTIVATION; GROWTH; STAT3; AZD1480; ROLES; TRANSDUCER; DISCOVERY; PATHWAYS; SURVIVAL;
D O I
10.1038/s41401-019-0254-4
中图分类号
O6 [化学];
学科分类号
0703 ;
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.
引用
收藏
页码:1578 / 1586
页数:9
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