PKC-zeta Aggravates Doxorubicin-Induced Cardiotoxicity by Inhibiting Wnt/beta-Catenin Signaling

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-zeta (PKC-zeta) 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-zeta induced cardiac hypertrophy by activating the inflammatory signaling pathway. This study focused on whether PKC-zeta played an important role in Dox-induced cardiotoxicity. We found that PKC-zeta phosphorylation was increased by Dox treatment in vivo and in vitro. PKC-zeta overexpression exacerbated Dox-induced cardiotoxicity. Conversely, knockdown of PKC-zeta by siRNA relieved Dox-induced cardiotoxicity. Similar results were observed when PKC-zeta enzyme activity was inhibited by its pseudosubstrate inhibitor, Myristoylated. PKC-zeta interacted with beta-catenin and inhibited Wnt/beta-catenin signaling pathway. Activation of Wnt/beta-catenin signaling by LiCl protected against Dox-induced cardiotoxicity. The Wnt/beta-catenin inhibitor XAV-939 aggravated Dox-caused decline of beta-catenin and cardiomyocyte apoptosis and mitochondrial damage. Moreover, activation of Wnt/beta-catenin suppressed aggravation of Dox-induced cardiotoxicity due to PKC-zeta overexpression. Taken together, our study revealed that inhibition of PKC-zeta activity was a potential cardioprotective approach to preventing Dox-induced cardiac injury.