title: Two naturally occurring terpenes, dehydrocostuslactone and costunolide, decrease intracellular GSH content and inhibit STAT3 activation.
abstract: The main purpose of the present study is to envisage the molecular mechanism of inhibitory action of dehydrocostuslactone (DCE) and costunolide (CS), two naturally occurring sesquiterpene lactones, towards the activation of signal transducer and activator of transcription 3 (STAT3). We report that, in human THP-1 cell line, they inhibit IL-6-elicited tyrosine phosphorylation of STAT3 and its DNA binding activity with EC(50) of 10 µM with concomitant down-regulation of the phosphorylation of the tyrosine Janus kinases JAK1, JAK2 and Tyk2. Furthermore, these compounds that contain an α-β-unsaturated carbonyl moiety and function as potent Michael reaction acceptor, induce a rapid drop in intracellular glutathione (GSH) concentration by direct interaction with it, thereby triggering S-glutathionylation of STAT3. Dehydrocostunolide (HCS), the reduced form of CS lacking only the α-β-unsaturated carbonyl group, fails to exert any inhibitory action. Finally, the glutathione ethylene ester (GEE), the cell permeable GSH form, reverts the inhibitory action of DCE and CS on STAT3 tyrosine phosphorylation. We conclude that these two sesquiterpene lactones are able to induce redox-dependent post-translational modification of cysteine residues of STAT3 protein in order to regulate its function.
authors.affiliation: Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Butturini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cavalieri
authors.forename: Alessandra Carcereri
authors.initials: AC
authors.lastname: de Prati
authors.forename: Elena
authors.initials: E
authors.lastname: Darra
authors.forename: Antonella
authors.initials: A
authors.lastname: Rigo
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shoji
authors.forename: Norie
authors.initials: N
authors.lastname: Murayama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Hisanori
authors.initials: H
authors.lastname: Suzuki
authors.forename: Sofia
authors.initials: S
authors.lastname: Mariotto
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D007783:Lactones; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D012717:Sesquiterpenes; C083030:dehydrocostus lactone; C002602:costunolide; D005978:Glutathione