title: Increased aerobic glycolysis is important for the motility of activated VSMC and inhibited by indirubin-3'-monoxime.
abstract: Increased aerobic glycolysis is a recognized feature of multiple cellular phenotypes and offers a potential point for drug interference, as pursued by anti-tumor agents targeting the Warburg effect. This study aimed at examining the role of aerobic glycolysis for migration of vascular smooth muscle cells (VSMC) and its susceptibility to the small molecule indirubin-3'-monoxime (I3MO). Activation of VSMC with platelet-derived growth factor (PDGF) resulted in migration and increased glycolytic activity which was accompanied by an increased glucose uptake and hexokinase (HK) 2 expression. Inhibition of glycolysis or hexokinase by pharmacological agents or siRNA-mediated knockdown significantly reduced the migratory behavior in VSMC without affecting cell viability or early actin cytoskeleton rearrangement. I3MO, previously recognized as inhibitor of VSMC migration, was able to counteract the PDGF-activated increase in glycolysis and HK2 abundance. Activation of signal transducer and activator of transcription (STAT) 3 could be identified as crucial event in upregulation of HK2 and glycolytic activity in PDGF-stimulated VSMC and as point of interference for I3MO. I3MO did not inhibit hypoxia-inducible factor (HIF)1α-dependent transcription nor influence miRNA 143 levels, other potential regulators of HK2 levels. Overall, we demonstrate that increased aerobic glycolysis is an important factor for the motility of activated VSMC and that the anti-migratory property of I3MO may partly depend on impairment of glycolysis via a compromised STAT3/HK2 signaling axis.
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria. Electronic address: elke.heiss@univie.ac.at.
authors.forename: Elke H
authors.initials: EH
authors.lastname: Heiss
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schachner
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo, 5, 35131 Padova, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Donati
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Christoph S
authors.initials: CS
authors.lastname: Grojer
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Verena M
authors.initials: VM
authors.lastname: Dirsch
mesh_terms: D000818:Animals; D016466:CHO Cells; D002465:Cell Movement / Q000187:drug effects*; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006019:Glycolysis / Q000187:drug effects*; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
chemical_list: D007211:Indoles; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D010091:Oximes; D010982:Platelet-Derived Growth Factor; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; C474021:indirubin-3'-monoxime; D006593:Hexokinase; D010100:Oxygen
keywords: Aerobic glycolysis; Hexokinase; Indirubin-3′ monoxime; Migration; VSMC