Study of ER stress and apoptotic proteins in the heart and tumor exposed to doxorubicin

Biochim Biophys Acta Mol Cell Res. 2021 Jun;1868(7):119039. doi: 10.1016/j.bbamcr.2021.119039. Epub 2021 Apr 17.

Abstract

Although a high cumulative dose of Doxorubicin (Dox) is known to cause cardiotoxicity, there is still a lack of understanding of the subcellular basis of this drug-induced cardiomyopathy. Differential effects of Dox on mitochondria and endoplasmic reticulum (ER) were examined in cardiomyocytes, tumor cells, implanted tumors and hearts of normal as well as tumor-bearing animals. Dox increased mitochondrial (Mito) Bax activation at 3 h in the cardiomyocyte without change in the DNA damage inducible transcriptor-3 (DDIT3) expression in the ER. Increased DDIT3 in these Dox-treated cardiomyocytes at 24 h suggested that increased MitoBax may have promoted ER stress related changes in DDIT3. Dissociation of immunoglobulin-binding protein (Bip) from activating transcription factor 6 (ATF6)-Bip complex in the ER was observed as an adaptive response to Dox. In contrast, breast cancer MCF7 cells showed an ER stress response to Dox with increased DDIT3 as early as 3 h which may have triggered a positive feedback activation of ATF6 at 12 and 24 h and promoted Calnexin. At these later time points, increased Bax activation in cancer cells suggested that MitoBax may be controlled by DDIT3 or by Calnexin. DDIT3 response in tumors was evoked by Dox, however this response was inversely correlated with increased Bip and Bax expression in hearts from tumor bearing animals. It is suggested that in Dox-induced cardiotoxicity both mitochondrial and ER stresses play an integral role through a mutual interaction where an inhibition of DDIT3 or Calnexin may also be crucial to achieve Dox resistance in cardiomyocytes.

Keywords: Activating transcription factor 6; Apoptosis; DNA damage inducible transcriptor-3; Dox-induced cardiomyopathy; Immunoglobulin binding protein; Mitochondrial Bax.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / metabolism
  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins / metabolism
  • Cardiomyopathies / metabolism
  • Cardiotoxicity / pathology
  • Cell Line, Tumor
  • Doxorubicin / metabolism
  • Doxorubicin / pharmacology
  • Doxorubicin / toxicity*
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / physiology
  • Endoplasmic Reticulum Stress / drug effects*
  • Endoplasmic Reticulum Stress / physiology
  • Female
  • Humans
  • Male
  • Mitochondria / metabolism
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / physiology
  • Neoplasms / metabolism
  • Neoplasms / physiopathology
  • Oxidative Stress / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism
  • Transcription Factor CHOP / metabolism

Substances

  • Activating Transcription Factor 6
  • Apoptosis Regulatory Proteins
  • Reactive Oxygen Species
  • Transcription Factor CHOP
  • Doxorubicin