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Transcriptomic profiling reveals p53 as a key regulator of doxorubicin-induced cardiotoxicity.

ABSTRACT: Doxorubicin is an important anticancer drug in the clinic. Unfortunately, it causes cumulative and dose-dependent cardiotoxic side effects. As the population of cancer survivors who have been exposed to treatment continues to grow, there is increased interest in assessing the long-term cardiac effects of doxorubicin and understanding the underlying mechanisms at play. In this study, we investigated doxorubicin-induced transcriptomic changes using RNA-sequencing (RNAseq) and a cellular model comprised of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Analyses of predicted upstream regulators identified the p53 protein as a key regulator of transcriptomic changes induced by doxorubicin. Clustering and pathway analyses showed that increased death receptor (DR) expression and enrichment of the extrinsic apoptotic pathway are significantly associated with doxorubicin-induced cardiotoxicity. Increased expression of p53 and DRs were confirmed via immunoblotting. Our data pinpoints increased DR expression as an early transcriptomic indicator of cardiotoxicity, suggesting that DR expression might function as a predictive biomarker for cardiac damage.

SUBMITTER: McSweeney KM

PROVIDER: S-EPMC6561911 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Transcriptomic profiling reveals p53 as a key regulator of doxorubicin-induced cardiotoxicity.

McSweeney K Melodi KM Bozza William P WP Alterovitz Wei-Lun WL Zhang Baolin B

Cell death discovery 20190612

Doxorubicin is an important anticancer drug in the clinic. Unfortunately, it causes cumulative and dose-dependent cardiotoxic side effects. As the population of cancer survivors who have been exposed to treatment continues to grow, there is increased interest in assessing the long-term cardiac effects of doxorubicin and understanding the underlying mechanisms at play. In this study, we investigated doxorubicin-induced transcriptomic changes using RNA-sequencing (RNAseq) and a cellular model comp ...[more]

PMID: 31231550

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Project description:Doxorubicin (DOX), the anthracycline chemotherapeutic agent, is widely used for the treatment of various cancers. However, its clinical application is compromised by dose-dependent and fatal cardiotoxicity. This study is aimed at investigating the cardioprotective effects of Qishen granule (QSG) and the specific mechanism by which QSG alleviates DOX-induced cardiotoxicity (DIC) and providing an alternative for the treatment of DIC. We first evaluated the cardioprotective effects of QSG in a DIC mouse model, and the obtained results showed that QSG significantly protected against DOX-induced myocardial structural and functional damage, mitochondrial oxidative damage, and apoptosis. Subsequently, after a comprehensive understanding of the specific roles and recent developments of p53-mediated mitochondrial quality control mechanisms in DIC, we investigated whether QSG acted on MDM2 to regulate the activity of p53 and downstream mitophagy and mitochondrial biogenesis. The in vivo results showed that DOX inhibited mitochondrial biogenesis and blocked mitophagy in the mouse myocardium, while QSG reversed these effects. Mechanistically, we combined nutlin-3, which inhibits the binding of p53 and MDM2, with DOX and QSG and evaluated their influence on mitophagy and mitochondrial biogenesis in H9C2 cardiomyocytes. The obtained results showed that both DOX and nutlin-3 substantially inhibited mitophagy and mitochondrial biogenesis and induced mitochondrial oxidative damage and apoptosis, which could be partially recovered by QSG. Importantly, the immunoprecipitation results showed that QSG promoted the binding of MDM2 to p53, thus decreasing the level of p53 protein and the binding of p53 to Parkin. Collectively, QSG could promote the degradation of p53 by enhancing the binding of MDM2 to the p53 protein, resulting in the reduced binding of p53 to the Parkin protein, thus improving Parkin-mediated mitophagy. Increased degradation of p53 protein by QSG simultaneously enhanced mitochondrial biogenesis mediated by PGC-1α. Ultimately, QSG relieved DOX-induced mitochondrial oxidative damage and apoptosis by coordinating mitophagy and mitochondrial biogenesis.

Dataset Information

Transcriptomic profiling reveals p53 as a key regulator of doxorubicin-induced cardiotoxicity.

Publications

Transcriptomic profiling reveals p53 as a key regulator of doxorubicin-induced cardiotoxicity.

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