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

doi:10.1038/s41401-019-0254-4

	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
	Shan, Hui 2,4; Yao, Sheng 1,3,4; Ye, Yang 1,3,4; Yu, Qiang 2,4
刊名	ACTA PHARMACOLOGICA SINICA
	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.
资助项目	National Natural Science Foundation of China[81673465]
WOS关键词	JANUS KINASE FAMILY ; ACTIVATION ; GROWTH ; STAT3 ; AZD1480 ; ROLES ; TRANSDUCER ; DISCOVERY ; PATHWAYS ; SURVIVAL
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000500546400008
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/282072]
专题	中国科学院上海药物研究所
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.