Long noncoding RNA NONMMUT015745 inhibits doxorubicin-mediated cardiomyocyte apoptosis by regulating Rab2A-p53 axis

Abstract

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.

Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis

“…Additionally, DOX-induced oxidative stress stimulates TNF-α release, which activates several signaling pathways containing the nuclear factor kappa B (NF-κβ) inflammatory pathway [ 6 ]. In addition, DOX has a powerful apoptotic effect, where it mainly affects the mitochondrial pathway [ 7 ].…”

TGFB2-AS1 binding to MED1 promotes doxorubicin-induced cardiomyocyte apoptosis via BMP7 pathway

“…Recent studies found the role of long non-coding RNA in doxorubicin-induced cardiomyopathy, lncRNA NONMMUT015745 inhibits doxorubicin-mediated cardiomyocytes apoptosis by regulating the Rab2A-p53 axis [27], METTL14 silencing suppresses the ferroptosis of cardiomyocyte in doxorubicin-induced mice[28].TGFB2-AS1 has been reported in breast cancer, glioma, lung adenocarcinoma, gastric cancer, and other tumor diseases, and more importantly, the limited molecular biological role of TGFB2-AS1 in some diseases has been illustrated [29]. Studies have shown that mutations in the TGFBR1 and TGFB2-AS1 genes were associated with myopia in preschoolers, mediated by the TGF-β signaling pathway [30]; loss of TGFB2-AS1 signi cantly promoted Apoptosis of HepG2 liver cancer cells and inhibited migration and invasion [31], and TGFB2-AS1 interacted with the Core subunit of SWI/SNF complex, SMARCA4 to inhibit the expression of target genes TGFB2 and SOX2, ultimately inhibiting the breast Cancer progression [32].…”

Therapeutic potential of Ganoderma lucidum polysaccharide peptide in Doxorubicin-induced nephropathy: modulation of renin-angiotensin system and proteinuria

“…Previous research has shown that DOX causes apoptosis (Cai et al, 2022). To determine whether GL-PP could prevent DOX-induced cell death, we examined expression of apoptosis-related proteins after GL-PP treatment in cells exposed to DOX.…”