Bigelovin inhibits STAT3 signaling by inactivating JAK2 and induces apoptosis in human cancer cells

doi:10.1038/aps.2014.143

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Bigelovin inhibits STAT3 signaling by inactivating JAK2 and induces apoptosis in human cancer cells
	Zhang, Hao-hao 1; Kuang, Shan 1; Wang, Ying 1; Sun, Xiao-xiao 1; Gu, Yuan 1; Hu, Li-hong 2; Yu, Qiang1
刊名	ACTA PHARMACOLOGICA SINICA
	2015-04
卷号	36 期号:4 页码:507-516
关键词	apoptosis tumor cell line Chinese herbal drugs Inula hupehensis neoplasms STAT3 transcription factors Janus kinase 2 DTT signal transduction bigelovin interleukin-6 sesquiterpenes
ISSN号	1671-4083
DOI	10.1038/aps.2014.143
文献子类	Article
英文摘要	Aim: To study the function and mechanism of bigelovin, a sesquiterpene lactone from the flower of Chinese herb Inula hupehensis, in regulating JAK2/STAT3 signaling and cancer cell growth. Methods: HepG2 cells stably transfected with the STAT3-responsive firefly luciferase reporter plasmid (HepG2/STAT3 cells), and a panel of human cancer cell lines were used to identify active compounds. Cell viability was measured using MTT assay. Western blotting was used to detect protein expression and phosphorylation. Kinase assays were performed and the reaction between bigelovin and thiol-containing compounds was analyzed with LC-MS. Results: Bigelovin (1-50 mu mol/L) dose-dependently inhibited the IL-6-induced STAT3 activation in HepG2/STAT3 cells (IC50=3.37 mu mol/L) and the constitutive STAT3 activation in A549 and MDA-MB-468 cells. Furthermore, bigelovin dose-dependently inhibited JAK2 phosphorylation in HeLa and MDA-MB-468 cells, as well as the enzymatic activity of JAK2 in vitro (IC50=44.24 mu mol/L). Pretreatment of the cells with DTT (500 mu mol/L) or GSH (500 mu mol/L) eliminated the inhibitory effects of bigelovin on the IL-6-induced and the constitutive STAT3 activation. The results in LC-MS analysis suggested that bigelovin might react with cysteine residues of JAK2 leading to inactivation of JAK2. Bigelovin (5 and 20 mu mol/L) had no effects on the signaling pathways of growth factors EGF, PDGF or insulin. Finally, bigelovin suppressed the cell viability and induced apoptosis in 10 different human cancer cell lines, particularly those with constitutively activated STAT3. Conclusion: Bigelovin potently inhibits STAT3 signaling by inactivating JAK2, and induces apoptosis of a variety of human cancer cells in vitro.
资助项目	China Ministry of Science and Technology Key New Drug Creation and Manufacturing Program[2013ZX09102015] ; China Ministry of Science and Technology Research[2013ZX10002010-009] ; National Natural Science Foundation of China[81302792] ; National Natural Science Foundation of China[81373447] ; National Natural Science Foundation of China[91213304] ; China National Key Basic Research Program[2012CB910704] ; China National Key Basic Research Program[2013CB910900]
WOS关键词	KAPPA-B KINASE ; CONSTITUTIVE ACTIVATION ; MYELOPROLIFERATIVE DISORDERS ; TRANSCRIPTION FACTORS ; CONFERS RESISTANCE ; POLYCYTHEMIA-VERA ; TYROSINE KINASES ; CARCINOMA CELLS ; HUMAN LEUKEMIA ; MYELOMA CELLS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000352203300011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276588]
专题	药理学第一研究室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
通讯作者	Yu, Qiang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Tumor Pharmacol, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Hao-hao,Kuang, Shan,Wang, Ying,et al. Bigelovin inhibits STAT3 signaling by inactivating JAK2 and induces apoptosis in human cancer cells[J]. ACTA PHARMACOLOGICA SINICA,2015,36(4):507-516.
APA	Zhang, Hao-hao.,Kuang, Shan.,Wang, Ying.,Sun, Xiao-xiao.,Gu, Yuan.,...&Yu, Qiang.(2015).Bigelovin inhibits STAT3 signaling by inactivating JAK2 and induces apoptosis in human cancer cells.ACTA PHARMACOLOGICA SINICA,36(4),507-516.
MLA	Zhang, Hao-hao,et al."Bigelovin inhibits STAT3 signaling by inactivating JAK2 and induces apoptosis in human cancer cells".ACTA PHARMACOLOGICA SINICA 36.4(2015):507-516.