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

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Zhang, Hao-hao Kuang, Shan Wang, Ying Sun, Xiao-xiao Gu, Yuan Hu, Li-hong Yu, Qiang
Description	Country affiliation: China Author Affiliation: Zhang HH ( Department of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.); Kuang S ( Department of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.); Wang Y ( Department of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.); Sun XX ( Department of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.); Gu Y ( Department of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.); Hu LH ( State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.); Yu Q ( Department of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.)
Abstract	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 µmol/L) dose-dependently inhibited the IL-6-induced STAT3 activation in HepG2/STAT3 cells (IC50=3.37 µmol/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 µmol/L). Pretreatment of the cells with DTT (500 µmol/L) or GSH (500 µmol/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 µmol/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.
File Format	HTM / HTML
ISSN	16714083
e-ISSN	17457254
DOI	10.1038/aps.2014.143
Journal	Acta Pharmacologica Sinica
Issue Number	4
Volume Number	36
Language	English
Publisher	Macmillan Publishers Limited
Publisher Date	2015-04-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Pharmacology Antineoplastic Agents, Phytogenic Pharmacology Apoptosis Drug Effects Janus Kinase 2 Metabolism Lactones Neoplasms Drug Therapy Stat3 Transcription Factor Sesquiterpenes Signal Transduction Chemistry Cell Line, Tumor Hep G2 Cells Inula Pathology Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Pharmacology Pharmacology (medical)

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