PKC-ζ Aggravates Doxorubicin-Induced Cardiotoxicity by Inhibiting Wnt/β-Catenin Signaling.

Yan-Jun Cao,Jing-Yan Li,Pan-Xia Wang,Pei-Qing Liu,Zhi-Rong Lin,Wen-Jing Yu,Ji-Guo Zhang,Jing Lu

doi:10.3389/fphar.2022.798436

Abstract

Doxorubicin (Dox) is a chemotherapeutic drug used to treat a wide range of cancers, but its clinical application is limited due to its cardiotoxicity. Protein kinase C-ζ (PKC-ζ) is a serine/threonine kinase belonging to atypical protein kinase C (PKC) subfamily, and is activated by its phosphorylation. We and others have reported that PKC-ζ induced cardiac hypertrophy by activating the inflammatory signaling pathway. This study focused on whether PKC-ζ played an important role in Dox-induced cardiotoxicity. We found that PKC-ζ phosphorylation was increased by Dox treatment in vivo and in vitro. PKC-ζ overexpression exacerbated Dox-induced cardiotoxicity. Conversely, knockdown of PKC-ζ by siRNA relieved Dox-induced cardiotoxicity. Similar results were observed when PKC-ζ enzyme activity was inhibited by its pseudosubstrate inhibitor, Myristoylated. PKC-ζ interacted with β-catenin and inhibited Wnt/β-catenin signaling pathway. Activation of Wnt/β-catenin signaling by LiCl protected against Dox-induced cardiotoxicity. The Wnt/β-catenin inhibitor XAV-939 aggravated Dox-caused decline of β-catenin and cardiomyocyte apoptosis and mitochondrial damage. Moreover, activation of Wnt/β-catenin suppressed aggravation of Dox-induced cardiotoxicity due to PKC-ζ overexpression. Taken together, our study revealed that inhibition of PKC-ζ activity was a potential cardioprotective approach to preventing Dox-induced cardiac injury.

Highlights

Doxorubicin (Dox) is a widely used chemotherapeutic agent for treatment of leukemia, lymphoma, neuroblastoma, and other human cancers (Carvalho et al, 2014)
This study explored the role of Protein kinase C-ζ (PKC-ζ) in Dox-induced cardiotoxicity and underlying mechanisms
To explore the role of protein kinase C (PKC)-ζ in Dox-induced cardiac injury, we examined the change of PKC-ζ phosphorylation level in vivo and in vitro

Summary

INTRODUCTION

Doxorubicin (Dox) is a widely used chemotherapeutic agent for treatment of leukemia, lymphoma, neuroblastoma, and other human cancers (Carvalho et al, 2014). The serious cardiac side effects of Dox, including cardiomyopathy, arrhythmia, and congestive heart failure, limit its cumulative therapeutic dose in clinical application (Wallace et al, 2020) These cardiotoxic effects mainly stem from mitochondrial dysfunction (Wenningmann et al, 2019), autophagy (Bartlett et al, 2017), oxidative stress (Songbo et al, 2019), apoptosis (Takemura and Fujiwara, 2007), and impairment of calcium homeostasis PKC-ζ knockdown have been reported to reverse oxidized low-density lipoprotein lipotoxicity in cardiomyocytes (Chen et al, 2017) These findings highlight the crucial role of PKC-ζ in cardiovascular diseases, but its effect on Dox-induced cardiotoxicity remains unknown. PKC-ζ-based intervention was a potential strategy for alleviating Dox-induced cardiotoxicity

MATERIALS AND METHODS

RESULTS

DISCUSSION

ETHICS STATEMENT