12/15-Lipoxygenase Contributes to Platelet-derived Growth Factor-induced Activation of Signal Transducer and Activator of Transcription 3

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 import...

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Bibliographic Details
Published in:The Journal of biological chemistry 2013-12, Vol.288 (49), p.35592-35603
Main Authors: Blažević, Tina, Schwaiberger, Andrea V., Schreiner, Cornelia E., Schachner, Daniel, Schaible, Anja M., Grojer, Christoph S., Atanasov, Atanas G., Werz, Oliver, Dirsch, Verena M., Heiss, Elke H.
Format: Article
Language:English
Subjects:
Animals
Arachidonate 12-Lipoxygenase - genetics
Arachidonate 12-Lipoxygenase - metabolism
Arachidonate 15-Lipoxygenase - genetics
Arachidonate 15-Lipoxygenase - metabolism
Becaplermin
Cell Proliferation - drug effects
Cells, Cultured
Chemical Biology
Humans
Indirubin-3′-monoxime
Indoles - pharmacology
Lipoxygenase Pathway
Mice
Myocytes, Smooth Muscle - cytology
Myocytes, Smooth Muscle - drug effects
Myocytes, Smooth Muscle - metabolism
Oximes - pharmacology
Phosphorylation
Platelet-derived Growth Factor
Proto-Oncogene Proteins c-sis - metabolism
Rats
Reactive Oxygen Species - metabolism
Receptors, Platelet-Derived Growth Factor - metabolism
Redox Regulation
RNA, Small Interfering - genetics
Signal Transduction
src-Family Kinases - metabolism
STAT3
STAT3 Transcription Factor - metabolism
Vascular Smooth Muscle Cells
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Summary: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. Background: The small molecule indirubin-3′-monoxime (I3MO) inhibits activation of STAT3 in vascular smooth muscle cells, with an unresolved mechanism. Results: Activation of 12/15-lipoxygenase (LO) is crucial for PDGF-induced Src and STAT3 activation and is impaired by I3MO. Conclusion: I3MO interferes with PDGFR-Src-STAT3 signaling via impaired 12/15-LO activation. Significance: 12/15-LO is an important signaling hub within the PDGF-STAT3 pathway.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M113.489013