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

Yuheng Jiao,Song Zhang,Yafang Zha,Yanyan Li,Jian Wang,Jiayan Zhang

doi:10.3390/biom12020299

Yuheng Jiao, Song Zhang + Show 4 more

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https://doi.org/10.3390/biom12020299

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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.

Highlights

Doxorubicin, a broad-spectrum chemotherapeutic drug, is commonly used in the clinical treatment of cancer, with a potent curative effect [1]
The effect of DOX on ribonucleotide reductase M2 subunit (RRM2) expression was detected by qRT-PCR and Western blot
After the cells were treated with DOX (1 μmol/L) for 24 h, we found that the expression of RRM2 mRNA (Figure 1A) and protein levels (Figure 1C,D) were both decreased in primary cardiomyocytes, compared with the control group

Summary

Introduction

Doxorubicin, a broad-spectrum chemotherapeutic drug, is commonly used in the clinical treatment of cancer, with a potent curative effect [1]. Promoting DOX usage in clinical treatment still faces many obstacles, such as severe cardiotoxicity and heart failure [2,3]. It is believed that many factors are involved in its cardiotoxicity, such as the excessive accumulation of reactive oxygen species (ROS), calcium dysregulation, and disturbance of the apoptosis and autophagy pathways [4,5,6,7,8]. Current evidence has shown that the excessive accumulation of ROS is the culprit of DOX-induced cardiomyopathy, resulting in irreversible cardiac dysfunction [9]. DOX could lead to apoptosis without inducing ROS production and oxidative stress [10]. DOX-induced cardiotoxicity can be alleviated by inhibiting cardiomyocyte apoptosis [11]

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