Abstract
Signal abnormalities in human cells usually cause unexpected consequences for individual health. We focus on these kinds of events involved in JAK-STAT signal pathways, especially the ones triggered by aberrant activated STAT3, an oncoprotein which participates in essential processes of cell survival, growth and proliferation in many types of tumors, as well as immune diseases. By establishing a STAT3 signal based high-throughput drug screening system in human lung cancer A549 cells, we have screened a library from natural products which contained purified compounds from medicinal herbs. One compound, named Brevilin A, exhibited both strong STAT3 signal inhibition and STAT3 signal dependent cell growth inhibition. Further investigations revealed that Brevilin A not only inhibits STAT3 signaling but also STAT1 signaling for cytokines induced phosphorylation of STAT3 and STAT1 as well as the expression of their target genes. In addition, we found Brevilin A could attenuate the JAKs activity by blocking the JAKs tyrosine kinase domain JH1. The levels of cytokine induced phosphorylation of STATs and other substrates were dramatically reduced by treatment of Brevilin A. The roles of Brevilin A targeting on JAKs activity indicate that Brevilin A may not only be used as a STAT3 inhibitor but also a compound blocking other JAK-STAT hyperactivation. Thus, these findings provided a strong impetus for the development of selective JAK-STAT inhibitors and therapeutic drugs in order to improve survival of patients with hyperactivated JAKs and STATs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Biological Products / chemistry
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Biological Products / pharmacology*
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Biological Products / therapeutic use*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Crotonates / chemistry
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Crotonates / pharmacology*
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Crotonates / therapeutic use*
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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HEK293 Cells
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Humans
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Interleukin-6 / pharmacology
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Janus Kinases / antagonists & inhibitors*
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Janus Kinases / metabolism
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Neoplasms / drug therapy*
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Neoplasms / enzymology
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Neoplasms / metabolism*
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Neoplasms / pathology
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology
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Protein Structure, Tertiary
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Pyridones / pharmacology
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Pyrimidines / pharmacology
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STAT3 Transcription Factor / metabolism*
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Sesquiterpenes / chemistry
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Sesquiterpenes / pharmacology*
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Sesquiterpenes / therapeutic use*
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Signal Transduction / drug effects*
Substances
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Biological Products
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Crotonates
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Interleukin-6
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Protein Kinase Inhibitors
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Pyridones
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Pyrimidines
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STAT3 Transcription Factor
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Sesquiterpenes
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brevilin A
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Janus Kinases
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PD 180970
Grants and funding
This work was supported by grants 1104FK CA123 from The Science and Technology Support Project of Gansu Providence to Q.W.; 2009DFA30990 from the Ministry of Science and Technology of the People's Republic of China, 0708WCGA149 from the Gansu Provincial Science and Technology and 2009AA01A130 from National Natural Science Foundation of China to J.Y. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.