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Tripartite motif 25 ameliorates doxorubicin-induced cardiotoxicity by degrading p85α.

ABSTRACT: Doxorubicin (DOX)-based chemotherapy is widely used to treat malignant tumors; however, the cardiotoxicity induced by DOX restricts its clinical usage. A therapeutic dose of DOX can activate ubiquitin-proteasome system. However, whether and how ubiquitin-proteasome system brings out DOX-induced cardiotoxicity remains to be investigated. Here we conducted a proteomics analysis of a DOX-induced cardiotoxicity model to screen the potentially ubiquitination-related molecules. Dysregulated TRIM25 was found to contribute to the cardiotoxicity. In vivo and in vitro cardiotoxicity experiments revealed that TRIM25 ameliorated DOX-induced cardiotoxicity. Electron microscopy and endoplasmic reticulum stress markers revealed that TRIM25 mitigated endoplasmic reticulum stress and apoptosis in DOX-induced cardiomyocytes. Mechanistically, the Co-immunoprecipitation assays and CHX pulse-chase experiment determined that TRIM25 affected p85α stability and promoted its ubiquitination and degradation. This leads to increase of nuclear translocation of XBP-1s, which mitigates endoplasmic reticulum stress. These findings reveal that TRIM25 may have a therapeutic role for DOX-induced cardiotoxicity.

SUBMITTER: Shen Y

PROVIDER: S-EPMC9308790 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Tripartite motif 25 ameliorates doxorubicin-induced cardiotoxicity by degrading p85α.

Shen Yihui Y Zhang Hui H Ni Yangyue Y Wang Xuejun X Chen Yifan Y Chen Jiahui J Wang Yan Y Lin Jinyi J Xu Yuchen Y Zhao Jian-Yuan JY Cheng Leilei L

Cell death & disease 20220723 7

Doxorubicin (DOX)-based chemotherapy is widely used to treat malignant tumors; however, the cardiotoxicity induced by DOX restricts its clinical usage. A therapeutic dose of DOX can activate ubiquitin-proteasome system. However, whether and how ubiquitin-proteasome system brings out DOX-induced cardiotoxicity remains to be investigated. Here we conducted a proteomics analysis of a DOX-induced cardiotoxicity model to screen the potentially ubiquitination-related molecules. Dysregulated TRIM25 was ...[more]

PMID: 35871160

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Project description:Doxorubicin (DOX) is a potent anticancer drug with adverse cardiotoxic effects. Alginates are multifunctional biopolymers and polyelectrolytes derived from the cell walls of brown seaweeds. They are nontoxic, biocompatible, and biodegradable, and hence, utilized in several biomedical and pharmaceutical applications. Here, we investigated the potential cardioprotective effect of thermally treated sodium alginate (TTSA), which was extracted and purified from the seaweed Sargassum aquifolium, in treating acute DOX cardiotoxicity and apoptotic pathways in rats. UV-visible spectroscopy, Fourier-transform infrared, and nuclear magnetic resonance (1H-NMR) spectroscopy techniques were used to characterize TTSA. CK-MB and AST levels in sera samples were determined. The expression levels of Erk-2 (MAPK-1) and iNOS genes were investigated by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression levels of Erk-2, anti-apoptotic p53, and caspase-3 were analyzed using western blotting and ELISA. For the in vivo studies, sixty rats were randomly divided equally into six groups and treated with DOX, followed by TTSA. We revealed that treatment with TTSA, which has low molecular weight and enhanced antioxidant properties, improved DOX-mediated cardiac dysfunction and alleviated DOX-induced myocardial apoptosis. Furthermore, TTSA exhibited a cardioprotective effect against DOX-induced cardiac toxicity, indicated by the increased expression of MAPK-1 (Erk2) and iNOS genes, which are implicated in the adaptive responses regulating DOX-induced myocardial damage. Moreover, TTSA significantly (p < 0.05) suppressed caspase-3 and upregulated anti-apoptotic protein p53 expression. TTSA also rebalanced the cardiomyocyte redox potential by significantly (p < 0.05) increasing the levels of endogenous antioxidant enzymes, including catalase and superoxide dismutase. Our findings suggest that TTSA, particularly at a dose of 400 mg/kg b.w., is a potential prophylactic supplement for treating acute DOX-linked cardiotoxicity.

Dataset Information

Tripartite motif 25 ameliorates doxorubicin-induced cardiotoxicity by degrading p85α.

Publications

Tripartite motif 25 ameliorates doxorubicin-induced cardiotoxicity by degrading p85α.

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