ABSTRACT
The cancer clinical therapy of doxorubicin (Dox) treatment is limited by its life-threatening cardiotoxic effects. Dickkopf-1 (Dkk1), the founding and best-studied member of the Dkk family, 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 are poorly understood. Here, we found that the level of 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 active Dkk1 protein extracellularly. Conversely, adding specific antibody blocking extracellular Dkk1 attenuated the cardiotoxic response to Dox. 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 during Dox-induced cardiotoxicity, and the re-activation of β-catenin prevented the effect of overexpressed Dkk1 and Dox-induced cardiotoxicity. In conclusion, these results reveal the crucial role of the Dkk1–Wnt/β-catenin signaling axis in the process of Dox-induced cardiotoxicity and provide novel insights into the potential mechanism of cardiomyopathy caused by clinical application of Dox.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: L.L., J.L., P.L.; Methodology: L.L., Y.T., P.W., Z.G., Q.W., K.G., R.L.; Software: L.L., Y.T., P.W., Z.G.; Validation: L.L., J.L., P.L.; Formal analysis: L.L., J.L., P.L.; Investigation: L.L., P.W., Z.G., Q.W., K.G., R.L.; Resources: J.L., H.L., P.L.; Data curation: L.L., Y.T.; Writing - original draft: L.L.; Writing - review & editing: Y.T., J.L., P.L.; Visualization: L.L., P.W., Z.G.; Supervision: J.L., P.L.; Project administration: J.L., P.L.; Funding acquisition: J.L., H.L., P.L.
Funding
This research was supported by grants from the National Natural Science Foundation of China (81803521, 81872860, 81673433), Indigenous Innovative Research Team of Guangdong Province (2017BT01Y093), the National Major Special Projects for the Creation and Manufacture of New Drugs (2018ZX09301031-001), the Special Program for Applied Science and Technology of Guangdong Province (2015B020232009), the National Engineering and Technology Research Center for New Drug Druggability Evaluation (Seed Program of Guangdong Province, 2017B090903004), the Guangzhou Science and Technology Program Project (201604020121), Medical Scientific Research Foundation of Guangdong Province (A2018078), the Traditional Chinese Medicine Bureau of Guangdong Province (20191060) and the Natural Science Foundation of Guangdong Province (2017A030310542).
Supplementary information
Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.228478.supplemental
- Received December 2, 2018.
- Accepted April 9, 2019.
- © 2019. Published by The Company of Biologists Ltd
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