title: Inhibition of interleukin-3- and interferon- α-induced JAK/STAT signaling by the synthetic α-X-2',3,4,4'-tetramethoxychalcones α-Br-TMC and α-CF3-TMC.
abstract: The JAK/STAT pathway is an essential mediator of cytokine signaling, often upregulated in human diseases and therefore recognized as a relevant therapeutic target. We previously identified the synthetic chalcone α-bromo-2',3,4,4'-tetramethoxychalcone (α-Br-TMC) as a novel JAK2/STAT5 inhibitor. We also found that treatment with α-Br-TMC resulted in a downward shift of STAT5 proteins in SDS-PAGE, suggesting a post-translational modification that might affect STAT5 function. In the present study, we show that a single cysteine within STAT5 is responsible for the α-Br-TMC-induced protein shift, and that this modification does not alter STAT5 transcriptional activity. We also compared the inhibitory activity of α-Br-TMC to that of another synthetic chalcone, α-trifluoromethyl-2',3,4,4'-tetramethoxychalcone (α-CF3-TMC). We found that, like α-Br-TMC, α-CF3-TMC inhibits JAK2 and STAT5 phosphorylation in response to interleukin-3, however without altering STAT5 mobility in SDS-PAGE. Moreover, we demonstrate that both α-Br-TMC and α-CF3-TMC inhibit interferon-α-induced activation of STAT1 and STAT2, by inhibiting their phosphorylation and the expression of downstream interferon-stimulated genes. Together with the previous finding that α-Br-TMC and α-CF3-TMC inhibit the response to inflammation by inducing Nrf2 and blocking NF-κB activities, our data suggest that synthetic chalcones might be useful as anti-inflammatory, anti-cancer and immunomodulatory agents in the treatment of human diseases.
authors.forename: Belinda
authors.initials: B
authors.lastname: Jobst
authors.forename: Julia
authors.initials: J
authors.lastname: Weigl
authors.forename: Carina
authors.initials: C
authors.lastname: Michl
authors.forename: Fabio
authors.initials: F
authors.lastname: Vivarelli
authors.forename: Sophia
authors.initials: S
authors.lastname: Pinz
authors.forename: Sabine
authors.initials: S
authors.lastname: Amslinger
authors.forename: Anne
authors.initials: A
authors.lastname: Rascle
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D047188:Chalcones / Q000494:pharmacology*; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors*; D007377:Interleukin-3 / Q000037:antagonists & inhibitors*; D053614:Janus Kinase 2 / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D050799:STAT5 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D047188:Chalcones; D016898:Interferon-alpha; D007377:Interleukin-3; D050799:STAT5 Transcription Factor; C000594477:alpha-bromo-2',3,4,4'-tetramethoxychalcone; C000621074:alpha-trifluoromethyl-2',3,4,4'-tetramethoxychalcone; D053614:Janus Kinase 2