Inhibition of TBL1 cleavage alleviates doxorubicin-induced cardiomyocytes death by regulating the Wnt/β-catenin signal pathway

Author:

Lee Sun-Ho1,Lee Jangho2,Oh Jaewon3,Hwang Jin-Taek2,Lee Hae-Jeung4,Byun Hwa Kyung5,Kim Hyeong-Jin1,Suh David6,Yoon Ho-Geun17,Park Sahng Wook17,Kang Seok-Min3,Kwon Chulan6,Lee Seung-Hyun167,Choi Hyo-Kyoung2

Affiliation:

1. Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine , Seoul 03722 , Republic of Korea

2. Korea Food Research Institute , Jeollabuk-do 55365 , Republic of Korea

3. Division of Cardiology, Severance Cardiovascular Hospital, Cardiovascular Research Institute, Yonsei University College of Medicine , Seoul 03722 , Republic of Korea

4. Department of Food and Nutrition, Gachon University , Gyeonggi-do 13120 , Republic of Korea

5. Department of Radiation Oncology, Yonsei University College of Medicine , Seoul 03722 , Republic of Korea

6. Division of Cardiology, Department of Medicine, Johns Hopkins University , Baltimore, MD 21205 , USA

7. Institute of Genetic Science, Yonsei University College of Medicine , Seodaemun-gu, Seoul 03722 , Republic of Korea

Abstract

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.

Funder

National Research Foundation of Korea

Korean government

Main Research Program

Korea Food Research Institute

Ministry of Science and ICT

Korea Health Technology R&D Project

Korea Health Industry Development Institute

Ministry of Health & Welfare, the Republic of Korea

National Stem Cell Bank of Korea

Korea National Institute of Health

Catholic University

Publisher

Oxford University Press (OUP)

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