title: FL3, a Synthetic Flavagline and Ligand of Prohibitins, Protects Cardiomyocytes via STAT3 from Doxorubicin Toxicity.
abstract: OBJECTIVE
  The clinical use of doxorubicin for the treatment of cancer is limited by its cardiotoxicity. Flavaglines are natural products that have both potent anticancer and cardioprotective properties. A synthetic analog of flavaglines, FL3, efficiently protects mice from the cardiotoxicity of doxorubicin. The mechanism underlying this cardioprotective effect has yet to be elucidated.
  
  
  RESULTS
  Here, we show that FL3 binds to the scaffold proteins prohibitins (PHBs) and thus promotes their translocation to mitochondria in the H9c2 cardiomyocytes. FL3 induces heterodimerization of PHB1 with STAT3, thereby ensuring cardioprotection from doxorubicin toxicity. This interaction is associated with phosphorylation of STAT3. A JAK2 inhibitor, WP1066, suppresses both the phosphorylation of STAT3 and the protective effect of FL3 in cardiomyocytes. The involvement of PHBs in the FL3-mediated cardioprotection was confirmed by means of small interfering RNAs (siRNAs) targeting PHB1 and PHB2. The siRNA knockdown of PHBs inhibits both phosphorylation of STAT3 and the cardioprotective effect of FL3.
  
  
  CONCLUSIONS
  Activation of mitochondrial STAT3/PHB1 complex by PHB ligands may be a new strategy against doxorubicin-induced cardiotoxicity and possibly other cardiac problems.
authors.affiliation: GPCRs in cardiobiology and Metabolism team, UMR 7242, CNRS-University of Strasbourg, LabEx Medalis, Strasbourg School of Biotechnology, Illkirch, France.
authors.forename: Rehana
authors.initials: R
authors.lastname: Qureshi
authors.affiliation: GPCRs in cardiobiology and Metabolism team, UMR 7242, CNRS-University of Strasbourg, LabEx Medalis, Strasbourg School of Biotechnology, Illkirch, France.
authors.forename: Onur
authors.initials: O
authors.lastname: Yildirim
authors.affiliation: GPCRs in cardiobiology and Metabolism team, UMR 7242, CNRS-University of Strasbourg, LabEx Medalis, Strasbourg School of Biotechnology, Illkirch, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Gasser
authors.affiliation: Laboratory of Therapeutic Innovation (UMR 7200), Faculty of Pharmacy, University of Strasbourg-CNRS, Illkirch, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Basmadjian
authors.affiliation: Laboratory of Therapeutic Innovation (UMR 7200), Faculty of Pharmacy, University of Strasbourg-CNRS, Illkirch, France.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: GPCRs in cardiobiology and Metabolism team, UMR 7242, CNRS-University of Strasbourg, LabEx Medalis, Strasbourg School of Biotechnology, Illkirch, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Wilmet
authors.affiliation: Laboratory of Therapeutic Innovation (UMR 7200), Faculty of Pharmacy, University of Strasbourg-CNRS, Illkirch, France.|Sino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China.
authors.forename: Laurent
authors.initials: L
authors.lastname: Désaubry
authors.affiliation: GPCRs in cardiobiology and Metabolism team, UMR 7242, CNRS-University of Strasbourg, LabEx Medalis, Strasbourg School of Biotechnology, Illkirch, France.
authors.forename: Canan G
authors.initials: CG
authors.lastname: Nebigil
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology*; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology*; D066126:Cardiotoxicity; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008024:Ligands; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D000091402:Prohibitins; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D001572:Benzofurans; D002316:Cardiotonic Agents; D008024:Ligands; C000717332:Phb protein, rat; C000717333:Phb2 protein, mouse; D000091402:Prohibitins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D004317:Doxorubicin