1. Inhibition of TBL1 cleavage alleviates doxorubicin-induced cardiomyocytes death by regulating the Wnt/β-catenin signal pathway.
- Author
-
Lee SH, Lee J, Oh J, Hwang JT, Lee HJ, Byun HK, Kim HJ, Suh D, Yoon HG, Park SW, Kang SM, Kwon C, Lee SH, and Choi HK
- Subjects
- Humans, Animals, Cardiomyopathy, Dilated metabolism, Cardiomyopathy, Dilated pathology, Cardiomyopathy, Dilated chemically induced, Cardiomyopathy, Dilated genetics, Cardiomyopathy, Dilated enzymology, Cardiomyopathy, Dilated physiopathology, Male, Transducin metabolism, Transducin genetics, Disease Models, Animal, Mice, Inbred C57BL, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells drug effects, Induced Pluripotent Stem Cells enzymology, Induced Pluripotent Stem Cells pathology, Female, Case-Control Studies, Antibiotics, Antineoplastic pharmacology, Antibiotics, Antineoplastic toxicity, Doxorubicin pharmacology, Myocytes, Cardiac drug effects, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Myocytes, Cardiac enzymology, Wnt Signaling Pathway drug effects, Cardiotoxicity, Apoptosis drug effects, beta Catenin metabolism, beta Catenin genetics
- Abstract
Aims: Doxorubicin (DOX) is a widely used anthracycline anticancer agent; however, its irreversible effects on the heart can result in DOX-induced cardiotoxicity (DICT) after cancer treatment. Unfortunately, the pathophysiology of DICT has not yet been fully elucidated, and there are no effective strategies for its prevention or treatment. In this investigation, the novel role of transducin beta-like protein 1 (TBL1) in developing and regulating DICT was explored., Methods and Results: We observed a reduction in TBL1 protein expression levels as well as cleavage events in the transplanted cardiac tissues of patients diagnosed with Dilated Cardiomyopathy and DICT. It was revealed that DOX selectively induces TBL1 cleavage at caspase-3 preferred sites-D125, D136, and D215. Interestingly, overexpression of the uncleaved TBL1 mutant (TBL1uclv) variant reduced apoptosis, effectively preventing DOX-induced cell death. We confirmed that cleaved TBL1 cannot form a complex with β-catenin. As a result, Wnt reporter activity and Wnt target gene expression collectively indicate a decrease in Wnt/β-catenin signalling, leading to DICT progression. Furthermore, the cleaved TBL1 triggered DOX-induced abnormal electrophysiological features and disrupted calcium homeostasis. However, these effects were improved in TBL1uclv-overexpressing human-induced pluripotent stem cell-derived cardiomyocytes. Finally, in a DICT mouse model, TBL1uclv overexpression inhibited the DICT-induced reduction of cardiac contractility and collagen accumulation, ultimately protecting cardiomyocytes from cell death., Conclusion: Our findings reveal that the inhibition of TBL1 cleavage not only mitigates apoptosis but also enhances cardiomyocyte function, even in the context of DOX administration. Consequently, this study's results suggest that inhibiting TBL1 cleavage may be a novel strategy to ameliorate DICT., Competing Interests: Conflict of interests: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2024
- Full Text
- View/download PDF