RRM2 Alleviates Doxorubicin-Induced Cardiotoxicity through the AKT/mTOR Signaling Pathway
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 stu...
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MDPI AG
2022-02-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/2/299 |
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| author | Yuheng Jiao Yanyan Li Jiayan Zhang Song Zhang Yafang Zha Jian Wang |
| author_facet | Yuheng Jiao Yanyan Li Jiayan Zhang Song Zhang Yafang Zha Jian Wang |
| author_sort | Yuheng Jiao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T22:30:11Z |
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| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T22:30:11Z |
| publishDate | 2022-02-01 |
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| series | Biomolecules |
| spelling | doaj.art-bb7c4b6d81ea4084a1550f836a09d58d2023-11-23T18:59:39ZengMDPI AGBiomolecules2218-273X2022-02-0112229910.3390/biom12020299RRM2 Alleviates Doxorubicin-Induced Cardiotoxicity through the AKT/mTOR Signaling PathwayYuheng Jiao0Yanyan Li1Jiayan Zhang2Song Zhang3Yafang Zha4Jian Wang5Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, ChinaDepartment of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai 200092, ChinaDepartment of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, ChinaDepartment of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, ChinaDepartment of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, ChinaDepartment of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, ChinaDoxorubicin (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.https://www.mdpi.com/2218-273X/12/2/299RRM2doxorubicinAKT/mTOR pathwaycardiotoxicity |
| spellingShingle | Yuheng Jiao Yanyan Li Jiayan Zhang Song Zhang Yafang Zha Jian Wang RRM2 Alleviates Doxorubicin-Induced Cardiotoxicity through the AKT/mTOR Signaling Pathway Biomolecules RRM2 doxorubicin AKT/mTOR pathway cardiotoxicity |
| title | RRM2 Alleviates Doxorubicin-Induced Cardiotoxicity through the AKT/mTOR Signaling Pathway |
| title_full | RRM2 Alleviates Doxorubicin-Induced Cardiotoxicity through the AKT/mTOR Signaling Pathway |
| title_fullStr | RRM2 Alleviates Doxorubicin-Induced Cardiotoxicity through the AKT/mTOR Signaling Pathway |
| title_full_unstemmed | RRM2 Alleviates Doxorubicin-Induced Cardiotoxicity through the AKT/mTOR Signaling Pathway |
| title_short | RRM2 Alleviates Doxorubicin-Induced Cardiotoxicity through the AKT/mTOR Signaling Pathway |
| title_sort | rrm2 alleviates doxorubicin induced cardiotoxicity through the akt mtor signaling pathway |
| topic | RRM2 doxorubicin AKT/mTOR pathway cardiotoxicity |
| url | https://www.mdpi.com/2218-273X/12/2/299 |
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