Cai Hongjing, Tian Pengchao, Ju Jie, Wang Tao, Chen Xinzhe, Wang Kai, Wang Fei, Yu Xue, Wang Shaocong, Wang Yin, Shan Chan, Li Peifeng
Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China.
Department of Pathophysiology, Binzhou Medical University, Yantai, China.
Cell Death Discov. 2022 Aug 16;8(1):364. doi: 10.1038/s41420-022-01144-9.
Doxorubicin (DOX) is an efficacious and widely used drug for human malignancy treatment, but its clinical application is limited due to side effects, especially cardiotoxicity. Our present study revealed that DOX could induce apoptosis in cardiomyocytes. Herein, we screened the dysregulated long noncoding RNAs (lncRNAs) in DOX-treated cardiomyocytes. Notably, overexpression of lncRNA NONMMUT015745 (lnc5745) could alleviate DOX-induced cardiomyocyte apoptosis both in vitro and in vivo. Conversely, silencing lnc5745 promotes cardiomyocyte apoptosis. Moreover, Rab2A, a direct target of lnc5745, possesses a protective effect in DOX-induced cardiotoxicity once knocked down. Importantly, we verified that the p53-related apoptotic signalling pathway was responsible for the lnc5745-mediated protective role against DOX-induced cardiomyocyte apoptosis. Mechanistically, Rab2A interacts with p53 and phosphorylated p53 on Ser 33 (p53 (Phospho-Ser 33)), promotes p53 phosphorylation, thereby activating the apoptotic pathway. Taken together, our results suggested that lnc5745 protects against DOX-induced cardiomyocyte apoptosis through suppressing Rab2A expression, modifying p53 phosphorylation, thereby regulating p53-related apoptotic signalling pathway. Our findings establish the functional mode of the lnc5745-Rab2A-p53 axis in DOX-induced cardiotoxicity. The development of new strategies targeting the lnc5745-Rab2A-p53 axis could attenuate DOX-induced cardiotoxicity, which is beneficial to its clinical anti-tumour application.
阿霉素（DOX）是一种用于人类恶性肿瘤治疗的有效且广泛使用的药物，但其临床应用因副作用尤其是心脏毒性而受到限制。我们目前的研究表明，DOX可诱导心肌细胞凋亡。在此，我们筛选了DOX处理的心肌细胞中失调的长链非编码RNA（lncRNA）。值得注意的是，lncRNA NONMMUT015745（lnc5745）的过表达在体外和体内均可减轻DOX诱导的心肌细胞凋亡。相反，沉默lnc5745会促进心肌细胞凋亡。此外，lnc5745的直接靶点Rab2A一旦被敲低，在DOX诱导的心脏毒性中具有保护作用。重要的是，我们证实p53相关的凋亡信号通路负责lnc5745介导的对DOX诱导的心肌细胞凋亡的保护作用。机制上，Rab2A与p53相互作用并使p53的丝氨酸33位点磷酸化（p53（磷酸化丝氨酸33）），促进p53磷酸化，从而激活凋亡途径。综上所述，我们的结果表明lnc5745通过抑制Rab2A表达、改变p53磷酸化，从而调节p53相关的凋亡信号通路，来保护心肌细胞免受DOX诱导的凋亡。我们的研究结果确立了lnc5745-Rab2A-p53轴在DOX诱导的心脏毒性中的功能模式。针对lnc5745-Rab2A-p53轴开发新策略可减轻DOX诱导的心脏毒性，这有利于其临床抗肿瘤应用。
