3deoxy216dihydroxynagilactoneeanaturalcompoundfrompodocarpusnagipreferentiallyinhibitsjak2stat3signalingbyallostericallyinteractingwiththeregulatorydomainofjak2andinducesapoptosisofcancercells

doi:10.1038/s41401-019-0254-4

	3deoxy216dihydroxynagilactoneeanaturalcompoundfrompodocarpusnagipreferentiallyinhibitsjak2stat3signalingbyallostericallyinteractingwiththeregulatorydomainofjak2andinducesapoptosisofcancercells
	Shan Hui 1; Yao Sheng 2; Ye Yang 2; Yu Qiang 1
刊名	actapharmacologicasinica
	2019
卷号	40 期号:12 页码:1578
关键词	JAK/STAT 3-deoxy-2β 16-dihydroxynagilactone E tyrosine kinase inhibitor allosteric inhibitor cancer
ISSN号	1671-4083
DOI	10.1038/s41401-019-0254-4
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-2β,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 μM. 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.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/280778]
专题	中国科学院上海药物研究所
作者单位	1.Division of Antitumor Pharmacology,Shanghai Institute of Materia Medica,Chinese Academy of Sciences 2.中国科学院上海药物研究所
推荐引用方式 GB/T 7714	Shan Hui,Yao Sheng,Ye Yang,et al. 3deoxy216dihydroxynagilactoneeanaturalcompoundfrompodocarpusnagipreferentiallyinhibitsjak2stat3signalingbyallostericallyinteractingwiththeregulatorydomainofjak2andinducesapoptosisofcancercells[J]. actapharmacologicasinica,2019,40(12):1578.
APA	Shan Hui,Yao Sheng,Ye Yang,&Yu Qiang.(2019).3deoxy216dihydroxynagilactoneeanaturalcompoundfrompodocarpusnagipreferentiallyinhibitsjak2stat3signalingbyallostericallyinteractingwiththeregulatorydomainofjak2andinducesapoptosisofcancercells.actapharmacologicasinica,40(12),1578.
MLA	Shan Hui,et al."3deoxy216dihydroxynagilactoneeanaturalcompoundfrompodocarpusnagipreferentiallyinhibitsjak2stat3signalingbyallostericallyinteractingwiththeregulatorydomainofjak2andinducesapoptosisofcancercells".actapharmacologicasinica 40.12(2019):1578.