RRM2 Alleviates Doxorubicin-Induced Cardiotoxicity through the AKT/mTOR Signaling Pathway

Abstract

Doxorubicin (DOX) is an effective chemotherapeutic agent that plays an unparalleled role in cancer treatment. However, its serious dose-dependent cardiotoxicity, which eventually contributes to irreversible heart failure, has greatly limited the widespread clinical application of DOX. A previous study has demonstrated that the ribonucleotide reductase M2 subunit (RRM2) exerts salutary effects on promoting proliferation and inhibiting apoptosis and autophagy. However, the specific function of RRM2 in DOX-induced cardiotoxicity is yet to be determined. This study aimed to elucidate the role and potential mechanism of RRM2 on DOX-induced cardiotoxicity by investigating neonatal primary cardiomyocytes and mice treated with DOX. Subsequently, the results indicated that RRM2 expression was significantly reduced in mice hearts and primary cardiomyocytes. Apoptosis and autophagy-related proteins, such as cleaved-Caspase3 (C-Caspase3), LC3B, and beclin1, were distinctly upregulated. Additionally, RRM2 deficiency led to increased autophagy and apoptosis in cells. RRM2 overexpression, on the contrary, alleviated DOX-induced cardiotoxicity in vivo and in vitro. Consistently, DIDOX, an inhibitor of RRM2, attenuated the protective effect of RRM2. Mechanistically, we found that AKT/mTOR inhibitors could reverse the function of RRM2 overexpression on DOX-induced autophagy and apoptosis, which means that RRM2 could have regulated DOX-induced cardiotoxicity through the AKT/mTOR signaling pathway. In conclusion, our experiment established that RRM2 could be a potential treatment in reversing DOX-induced cardiac dysfunction.

Identification of ferroptosis related markers by integrated bioinformatics analysis and In vitro model experiments in rheumatoid arthritis

“…7 A). In a concentration-dependent manner, DIDOX (inhibitor of RRM2) [ 36 ] restored the decreased viability of Erastin-treated C28/I2 cells ( P < 0.05, Fig. 7 A), implying the involvement of elevated RRM2 in ferroptosis.…”

Platelet-rich plasma ameliorates lipopolysaccharide-induced cardiac injury by inflammation and ferroptosis regulation

“…The AKT/mTOR signaling pathway plays a critical role in the development of multiple diseases and can regulate various mechanisms such as inflammation, oxidative stress, apoptosis, and autophagy ( Jiao et al, 2022 ; Zhang et al, 2022 ). At the same time, it has been reported that p-AKT and p-mTOR expressions were down-regulated in cardiomyocytes after treatment with LPS( Qi et al, 2021 ).…”

“…According to the previous method, we extracted proteins from cells and heart tissues for Western blot experiments ( Jiao et al, 2022 ). In short, we use 7.5–12.5% SDS-PAGE gel for protein separation and transfer it to PVDF membranes.…”

“…After treated with PRP and LPS, mice were anesthetized with isoflurane and the heart tissues were taken out. According to the previous experiments, we performed immunofluorescence to detect the content of ROS in tissues and Hematoxylin and eosin (H&E) staining ( Jiao et al, 2022 ). Briefly, fresh heart tissues were fixed in 4% paraformaldehyde and embedded in paraffin.…”

A new cell-free therapeutic strategy for liver regeneration: Human placental mesenchymal stem cell-derived extracellular vesicles

“…These findings suggested that circ-RBM23 could sponge miR-139-5p to inhibit its function in hepatocytes during the PH. Xiong et al 29 indicated that RRM2 activates the AKT pathway in renal cell carcinoma, and Jiao et al 30 found that RRM2 may regulate doxorubicin-induced cardiotoxicity through the AKT/mTOR signaling pathway. Huang et al 25 reported that AFAP1-AS1 upregulates RRM2 expression by sponging miR-139-5p in NSCLC cells.…”