title: 12/15-lipoxygenase contributes to platelet-derived growth factor-induced activation of signal transducer and activator of transcription 3.
abstract: We showed previously that the small molecule indirubin-3'-monoxime (I3MO) prevents vascular smooth muscle cell (VSMC) proliferation by selectively inhibiting signal transducer and activator of transcription 3 (STAT3). Looking for the underlying upstream molecular mechanism, we here reveal the important role of reactive oxygen species (ROS) for PDGF-induced STAT3 activation in VSMC. We show that neither NADPH-dependent oxidases (Noxes) nor mitochondria, but rather 12/15-lipoxygenase (12/15-LO) are pivotal ROS sources involved in the redox-regulated signal transduction from PDGFR to STAT3. Accordingly, pharmacological and genetic interference with 12/15-LO activity selectively inhibited PDGF-induced Src activation and STAT3 phosphorylation. I3MO is able to blunt PDGF-induced ROS and 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) production, indicating an inhibitory action of I3MO on 12/15-LO and consequently on STAT3. We identify 12/15-LO as a hitherto unrecognized signaling hub in PDGF-triggered STAT3 activation and show for the first time a negative impact of I3MO on 12/15-LO.
authors.affiliation: From the Department for Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria and.
authors.forename: Tina
authors.initials: T
authors.lastname: Blazevic
authors.forename: Andrea V
authors.initials: AV
authors.lastname: Schwaiberger
authors.forename: Cornelia E
authors.initials: CE
authors.lastname: Schreiner
authors.forename: Daniel
authors.initials: D
authors.lastname: Schachner
authors.forename: Anja M
authors.initials: AM
authors.lastname: Schaible
authors.forename: Christoph S
authors.initials: CS
authors.lastname: Grojer
authors.forename: Atanas G
authors.initials: AG
authors.lastname: Atanasov
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.forename: Verena M
authors.initials: VM
authors.lastname: Dirsch
authors.forename: Elke H
authors.initials: EH
authors.lastname: Heiss
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology; D010766:Phosphorylation; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C475064:12-15-lipoxygenase; D007211:Indoles; D010091:Oximes; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C474021:indirubin-3'-monoxime; D000077214:Becaplermin; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D017479:Receptors, Platelet-Derived Growth Factor; D019061:src-Family Kinases
keywords: Chemical Biology; Indirubin-3′-monoxime; Lipoxygenase Pathway; Platelet-derived Growth Factor; Redox Regulation; STAT3; Signal Transduction; Vascular Smooth Muscle Cells