Open AccessDkk1 exacerbates doxorubicin-induced cardiotoxicity by inhibiting Wnt/β-catenin signaling pathway
Author(s) -
Liang Liu,
Yalin Tu,
Jing Lu,
Panxia Wang,
Zhen Guo,
Wei Wang,
Kaiteng Guo,
Rui Lan,
Hong Li
Publication year - 2019
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.228478
Subject(s) - dkk1 , cardiotoxicity , wnt signaling pathway , doxorubicin , apoptosis , biology , cancer research , cardiomyopathy , pharmacology , microbiology and biotechnology , signal transduction , heart failure , medicine , chemotherapy , biochemistry , genetics
The cancer clinical therapy of Doxorubicin (Dox) is limited by its life-threatening cardiotoxic effects. Dickkopf-1 (Dkk1), the founding member of Dkk family, is best studied and functions as an antagonist of canonical Wnt/β-catenin. Dkk1 is considered to play a broad role in a variety of biological processes, but its effects on Dox-induced cardiomyopathy is poorly understood. Here, we found that Dkk1 was significantly increased in Dox-treated groups, and this increase exacerbated Dox-induced cardiomyocyte apoptosis and mitochondrial dysfunction. Overexpressing Dkk1 aggravated Dox-induced cardiotoxicity in H9C2 cells. Similar results were detected when adding the Dkk1 active protein extracellularly. Conversely, specific antibody blocking extracellular Dkk1 attenuated Dox-cardiotoxic response. Adenovirus encoding Dkk1 was transduced through intramyocardial injection and exacerbated Dox-induced cardiomyocyte apoptosis, mitochondrial damage and heart injury in vivo. Furthermore, Wnt/β-catenin signaling was inhibited in Dox-induced cardiotoxicity, the re-activation of β-catenin relieved overexpressed Dkk1 or Dox-induced cardiotoxicity. In conclusion, these results uncovered that the crucial role of Dkk1-Wnt/β-catenin signaling axis in the process of Dox-induced cardiotoxicity and provided novel insights into the potential mechanism on cardiomyopathy caused by clinical application of Dox.