title: Brevilin A, a novel natural product, inhibits janus kinase activity and blocks STAT3 signaling in cancer cells.
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.
authors.affiliation: School of Life Sciences, Lanzhou University, Lanzhou, Gansu, People's Republic of China.
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.forename: Yuping
authors.initials: Y
authors.lastname: Du
authors.forename: Jing
authors.initials: J
authors.lastname: Nan
authors.forename: Xinxin
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Qin
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Wang
authors.forename: Jianwen
authors.initials: J
authors.lastname: Hou
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Jinbo
authors.initials: J
authors.lastname: Yang
mesh_terms: D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003437:Crotonates / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011728:Pyridones / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001688:Biological Products; D003437:Crotonates; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; D012717:Sesquiterpenes; C585263:brevilin A; D053612:Janus Kinases; C410732:PD 180970