Doxorubicin induces protein ubiquitination and inhibits proteasome activity during cardiotoxicity

Sishi, Balindiwe J.N.; Loos, Ben; Rooyen, Jacques Van; Engelbrecht, Anna‐Mart

doi:10.1016/j.tox.2013.04.016

Cited by 40 publications

(25 citation statements)

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“…In subsequent microarray analysis comparing hearts from DOX‐treated WT and Nox2 −/− mice, cell death and survival functions were found to contribute the most relevant and significant network to this dataset, in accordance with many previous findings relating to transcriptional analysis of cardiac DOX effects, identifying the importance of the protein ubiquitination response amongst others (Deng et al, 2007; Thandavarayan et al, 2010; Tokarska‐Schlattner et al, 2010; Zhang et al, 2012; Sishi et al, 2013). In this study, we chose to specifically focus on the role of Nox2 as a novel aspect of DOX‐mediated signalling in this setting.…”

Section: Discussionsupporting

confidence: 89%

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

McLaughlin

Zhao

O’Neill

et al. 2017

British J Pharmacology

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Background and PurposeThe anthracycline doxorubicin (DOX), although successful as a first‐line cancer treatment, induces cardiotoxicity linked with increased production of myocardial ROS, with Nox2 NADPH oxidase‐derived superoxide reported to play a key role. The aim of this study was to identify novel mechanisms underlying development of cardiac remodelling/dysfunction further to DOX‐stimulated Nox2 activation.Experimental ApproachNox2−/− and wild‐type (WT) littermate mice were administered DOX (12 mg·kg−1 over 3 weeks) prior to study at 4 weeks. Detailed mechanisms were investigated in murine HL‐1 cardiomyocytes, employing a robust model of oxidative stress, gene silencing and pharmacological tools.Key ResultsDOX‐induced cardiac dysfunction, cardiomyocyte remodelling, superoxide production and apoptosis in WT mice were attenuated in Nox2−/− mice. Transcriptional analysis of left ventricular tissue identified 152 differentially regulated genes (using adjusted P < 0.1) in DOX‐treated Nox2−/− versus WT mice, and network analysis highlighted ‘Cell death and survival’ as the biological function most significant to the dataset. The mitochondrial membrane protein, mitofusin‐2 (Mfn2), appeared as a strong candidate, with increased expression (1.5‐fold), confirmed by qPCR (1.3‐fold), matching clear published evidence of promotion of cardiomyocyte cell death. In HL‐1 cardiomyocytes, targeted siRNA knockdown of Nox2 decreased Mfn2 protein expression, but not vice versa. While inhibition of Nox2 activity along with DOX treatment attenuated its apoptotic and cytotoxic effects, reduced apoptosis after Mfn2 silencing reflected a sustained cytotoxic response and reduced cell viability.Conclusions and ImplicationsDOX‐induced and Nox2‐mediated up‐regulation of Mfn2, rather than contributing to cardiomyocyte dysfunction through apoptotic pathways, appears to promote a protective mechanism.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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Section: Discussionsupporting

confidence: 89%

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

McLaughlin

Zhao

O’Neill

et al. 2017

British J Pharmacology

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“…The ubiquitinated cargo can interact with p62/ SQSTM1 and facilitate lysosomal targeting. Whether Dox-induced hyper-ubiquitination is due to massive damage to intracellular proteins, dysregulation in signaling pathways of the ubiquitination process, or because of decreased proteasomal degradation is still to be elucidated [103]. It is interesting to note that Dox affects various types of ubiquitin ligases in heart cells.…”

Section: Dox and The Autophagy Processmentioning

confidence: 99%

Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity

2017

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Doxorubicin (Dox) is a cytotoxic drug widely incorporated in various chemotherapy protocols. Severe side effects such as cardiotoxicity, however, limit Dox application. Mechanisms by which Dox promotes cardiac damage and cardiomyocyte cell death have been investigated extensively, but a definitive picture has yet to emerge. Autophagy, regarded generally as a protective mechanism that maintains cell viability by recycling unwanted and damaged cellular constituents, is nevertheless subject to dysregulation having detrimental effects for the cell. Autophagic cell death has been described, and has been proposed to contribute to Dox-cardiotoxicity. Additionally, mitophagy, autophagic removal of damaged mitochondria, is affected by Dox in a manner contributing to toxicity. Here we will review Dox-induced cardiotoxicity and cell death in the broad context of the autophagy and mitophagy processes.

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“…Previous observations have suggested that DOX mediates protein ubiquitination and degradation by the ubiquitin-proteasome system (UPS) (43,52). To understand the mechanism of FXN attenuation by DOX, our H9C2 cardiomyoblasts were treated with MG132, with or without the addition of DOX.…”

Section: Dox Induces Fxn Ubiquitination In H9c2 Cardiomyoblastsmentioning

confidence: 99%

The role of frataxin in doxorubicin-mediated cardiac hypertrophy

Mouli

Nanayakkara

AlAlasmari

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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(DOX) is a highly effective anti-neoplastic agent; however, its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. Previous studies have attributed the cause of DOXmediated cardiotoxicity to mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. The present study investigates the role of frataxin (FXN), a mitochondrial iron-sulfur biogenesis protein, and its role in development of DOX-mediated mitochondrial dysfunction. Athymic mice treated with DOX (5 mg/ kg, 1 dose/wk with treatments, followed by 2-wk recovery) displayed left ventricular hypertrophy, as observed by impaired cardiac hemodynamic performance parameters. Furthermore, we also observed significant reduction in FXN expression in DOX-treated animals and H9C2 cardiomyoblast cell lines, resulting in increased mitochondrial iron accumulation and the ensuing ROS formation. This observation was paralleled in DOX-treated H9C2 cells by a significant reduction in the mitochondrial bioenergetics, as observed by the reduction of myocardial energy regulation. Surprisingly, similar results were observed in our FXN knockdown stable cell lines constructed by lentiviral technology using short hairpin RNA. To better understand the cardioprotective role of FXN against DOX, we constructed FXN overexpressing cardiomyoblasts, which displayed cardioprotection against mitochondrial iron accumulation, ROS formation, and reduction of mitochondrial bioenergetics. Lastly, our FXN overexpressing cardiomyoblasts were protected from DOX-mediated cardiac hypertrophy. Together, our findings reveal novel insights into the development of DOX-mediated cardiomyopathy.anthracyclines; frataxin; cardiomyopathy; iron overload; mitochondrial damage; oxidative stress DOXORUBICIN (DOX) IS ONE OF the most widely used anti-neoplastic agents used for the treatment of a wide range of solid tumors and leukemia in children and adults (10,36,40). Despite its therapeutic usage, the clinical use of DOX is severely limited due to its cumulative dose-dependent cardiotoxicity, which develops over time into congestive heart failure (30). During this process, mitochondrial dysfunction has been observed to be fundamentally involved in the development of heart failure due to the dysregulation of mitochondrial bioenergetics and the generation of intracellular reactive oxygen species (ROS). The mechanism of DOX-induced cardiotoxicity at the cellular and subcellular levels is highly debatable. However, much attention has been attributed to the DOX-mediated formation of mitochondrial ROS. Although the role of iron has not been emphasized in the failing myocardial model, the role of iron in the formation of ROS has gained significance at the clinical setting with the usage of dexrazoxane (DXZ). DXZ, an iron chelator, is known to induce degradation of topo2␤ and prevent the DOX-mediated initiation of the DNA damage signal, H2AX-␥, in H9C2 cardiomyoblasts (28). However, the use of DXZ has been limited due to its interference with antitumor acti...

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Doxorubicin induces protein ubiquitination and inhibits proteasome activity during cardiotoxicity

Cited by 40 publications

References 50 publications

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity

The role of frataxin in doxorubicin-mediated cardiac hypertrophy

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