Cao Yan-Jun, Li Jing-Yan, Wang Pan-Xia, Lin Zhi-Rong, Yu Wen-Jing, Zhang Ji-Guo, Lu Jing, Liu Pei-Qing
National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
School of Pharmaceutical Science, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.
Front Pharmacol. 2022 Feb 14;13:798436. doi: 10.3389/fphar.2022.798436. eCollection 2022.
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 and . 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.
阿霉素（Dox）是一种用于治疗多种癌症的化疗药物，但其临床应用因心脏毒性而受到限制。蛋白激酶C-ζ（PKC-ζ）是一种属于非典型蛋白激酶C（PKC）亚家族的丝氨酸/苏氨酸激酶，通过磷酸化被激活。我们和其他人曾报道PKC-ζ通过激活炎症信号通路诱导心脏肥大。本研究聚焦于PKC-ζ在阿霉素诱导的心脏毒性中是否发挥重要作用。我们发现阿霉素处理会增加PKC-ζ的磷酸化。PKC-ζ的过表达加剧了阿霉素诱导的心脏毒性。相反，通过小干扰RNA（siRNA）敲低PKC-ζ可减轻阿霉素诱导的心脏毒性。当PKC-ζ的酶活性被其假底物抑制剂肉豆蔻酰化抑制时，也观察到了类似结果。PKC-ζ与β-连环蛋白相互作用并抑制Wnt/β-连环蛋白信号通路。氯化锂激活Wnt/β-连环蛋白信号可预防阿霉素诱导的心脏毒性。Wnt/β-连环蛋白抑制剂XAV-939加剧了阿霉素导致的β-连环蛋白减少、心肌细胞凋亡和线粒体损伤。此外，激活Wnt/β-连环蛋白可抑制因PKC-ζ过表达导致的阿霉素诱导的心脏毒性加重。综上所述，我们的研究表明抑制PKC-ζ活性是预防阿霉素诱导的心脏损伤的一种潜在心脏保护方法。
