Doxorubicin attenuates CHIP-guarded HSF1 nuclear translocation and protein stability to trigger IGF-IIR-dependent cardiomyocyte death

Cell Death Dis. 2016 Nov 3;7(11):e2455. doi: 10.1038/cddis.2016.356.

Abstract

Doxorubicin (DOX) is one of the most effective antitumor drugs, but its cardiotoxicity has been a major concern for its use in cancer therapy for decades. Although DOX-induced cardiotoxicity has been investigated, the underlying mechanisms responsible for this cardiotoxicity have not been completely elucidated. Here, we found that the insulin-like growth factor receptor II (IGF-IIR) apoptotic signaling pathway was responsible for DOX-induced cardiotoxicity via proteasome-mediated heat shock transcription factor 1 (HSF1) degradation. The carboxyl-terminus of Hsp70 interacting protein (CHIP) mediated HSF1 stability and nuclear translocation through direct interactions via its tetratricopeptide repeat domain to suppress IGF-IIR expression and membrane translocation under physiological conditions. However, DOX attenuated the HSF1 inhibition of IGF-IIR expression by diminishing the CHIP-HSF1 interaction, removing active nuclear HSF1 and triggering HSF1 proteasomal degradation. Overexpression of CHIP redistributed HSF1 into the nucleus, inhibiting IGF-IIR expression and preventing DOX-induced cardiomyocyte apoptosis. Moreover, HSF1A, a small molecular drug that enhances HSF1 activity, stabilized HSF1 expression and minimized DOX-induced cardiac damage in vitro and in vivo. Our results suggest that the cardiotoxic effects of DOX result from the prevention of CHIP-mediated HSF1 nuclear translocation and activation, which leads to an upregulation of the IGF-IIR apoptotic signaling pathway. We believe that the administration of an HSF1 activator or agonist may further protect against the DOX-induced cell death of cardiomyocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis / drug effects*
  • Cardiotoxins / toxicity
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Doxorubicin / pharmacology*
  • HSP70 Heat-Shock Proteins / metabolism
  • Heart Failure / diagnostic imaging
  • Heart Failure / metabolism
  • Heart Failure / pathology
  • Heat Shock Transcription Factors
  • Mice
  • Models, Biological
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding / drug effects
  • Protein Domains
  • Protein Stability / drug effects
  • Protein Transport / drug effects
  • Proteolysis / drug effects
  • Rats, Wistar
  • Receptor, IGF Type 2 / metabolism*
  • Transcription Factors / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cardiotoxins
  • DNA-Binding Proteins
  • HSP70 Heat-Shock Proteins
  • Heat Shock Transcription Factors
  • Hsf1 protein, rat
  • Receptor, IGF Type 2
  • Transcription Factors
  • Doxorubicin
  • Proteasome Endopeptidase Complex