期刊
ACTA PHARMACOLOGICA SINICA
卷 41, 期 9, 页码 1150-1157出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41401-020-0364-z
关键词
sFRP1; doxorubicin; Wnt/PCP-JNK pathway; apoptosis; Wnt/beta-catenin signaling; SP600125
资金
- National Natural Science Foundation of China [81872860, 81803521, 81673433, 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]
- YangFan Project of Guangdong Province [2014YT02S044]
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/beta-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 mu M) 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/beta-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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