Abstract
Doxorubicin (Dox) is an effective chemotherapy drug against a wide range of cancers, including both hematological and solid tumors. However, the serious cardiotoxic effect restricted its clinical application. We previously have illuminated the protective role of canonical Wnt/β-catenin signaling in Dox-induced cardiotoxicity. Secreted frizzled-related protein 1 (sFRP1) is one of the endogenous inhibitors of both canonical and noncanonical Wnt signaling. In this study, we investigated the relationship between sFRP1 and noncanonical Wnt/PCP-JNK (Wnt/planar cell polarity-c-Jun N-terminal kinase) pathway in Dox-induced cardiotoxicity in vitro and in vivo. We showed that treatment of H9c2 cardiac myoblasts with Dox (1 μM) time-dependently suppressed cell viability accompanied by significantly decreased sFRP1 protein level and increased Wnt/PCP-JNK signaling. Pretreatment with SP600125, the Wnt/PCP-JNK signaling inhibitor, attenuated Dox-induced apoptosis of H9c2 cells. Overexpression of sFRP1 protected H9c2 cells from Dox-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway. After intraperitoneal injection of a cumulative dose of 15 mg/kg Dox, rats displayed significant cardiac dysfunction; their heart showed inhibited Wnt/β-catenin signaling and activated Wnt/PCP-JNK signaling. These results suggest that sFRP1 may be a novel target for Dox-induced cardiotoxicity.
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Acknowledgements
This research was supported by grants from the National Natural Science Foundation of China (81872860, 81803521, 81673433, and 81572925), Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093), National Major Special Projects for the Creation and Manufacture of New Drugs (2019ZX09301104), Special Program for Applied Science and Technology of Guangdong Province (2015B020232009), National Engineering and Technology Research Center for New Druggability Evaluation (Seed Program of Guangdong Province, 2017B090903004), Guangzhou Science and Technology Program Project (201604020121), and YangFan Project of Guangdong Province (2014YT02S044).
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YHH designed and performed the research; Jie Liu, Jing Lu, and FHH wrote the paper; PXW analyzed the data; JXC and YG prepared the reagents; and JJW, WL, and PQL designed the research.
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Hu, Yh., Liu, J., Lu, J. et al. sFRP1 protects H9c2 cardiac myoblasts from doxorubicin-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway. Acta Pharmacol Sin 41, 1150–1157 (2020). https://doi.org/10.1038/s41401-020-0364-z
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DOI: https://doi.org/10.1038/s41401-020-0364-z
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