FL3, a Synthetic Flavagline and Ligand of Prohibitins, Protects Cardiomyocytes via STAT3 from Doxorubicin Toxicity

PLoS One. 2015 Nov 4;10(11):e0141826. doi: 10.1371/journal.pone.0141826. eCollection 2015.

Abstract

Aims: 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.

Methods and 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.

Conclusion: Activation of mitochondrial STAT3/PHB1 complex by PHB ligands may be a new strategy against doxorubicin-induced cardiotoxicity and possibly other cardiac problems.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Benzofurans / pharmacology*
  • Blotting, Western
  • Cardiotonic Agents / pharmacology*
  • Cardiotoxicity
  • Cells, Cultured
  • Doxorubicin / pharmacology*
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Ligands
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Phosphorylation / drug effects
  • Prohibitins
  • RNA, Small Interfering / genetics
  • Rats
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*

Substances

  • Antibiotics, Antineoplastic
  • Benzofurans
  • Cardiotonic Agents
  • Ligands
  • Phb protein, rat
  • Phb2 protein, mouse
  • Prohibitins
  • RNA, Small Interfering
  • Repressor Proteins
  • STAT3 Transcription Factor
  • Doxorubicin

Grants and funding

This work was supported by the “Association pour la Recherche sur le Cancer” (ARC, grant numbers 3940, SFI20111204054 and PJA 20141201909) and the “Agence National la Recherche” (ANR, grant number ANR-11-EMMA-021). This work has also been published within the LABEX ANR-10-LABX-0034_Medalis and received a financial support from the French government managed by Agence Nationale de la recherche under Programme d’investissement d׳avenir. Christine Basmadjian and Qian Zhao were supported by AAREC Filia Research and the Association Nationale de la Recherche et de la Technologie. Onur Yildirim received an Erasmus fellowship. This work was supported by grants from Centre National de la Recherche Scientifique, and Université de Strasbourg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.