한빛사논문
- 조회308
Sun-Ho Lee1†, Jangho Lee2†, Jaewon Oh3†, Jin-Taek Hwang2,4, Hae-Jeung Lee4, Hwa Kyung Byun5, Hyeong-Jin Kim1, David Suh6, Ho-Geun Yoon1,7, Sahng Wook Park1,7, Seok-Min Kang3, Chulan Kwon6, Seung-Hyun Lee1,6,7*, Hyo-Kyoung Choi2*
1Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
2Korea Food Research Institute, Jeollabuk-do 55365, Republic of Korea
3Division of Cardiology, Severance Cardiovascular Hospital, Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
4Department of Food and Nutrition, Gachon University, Gyeonggi-do 13120, Republic of Korea
5Department of Radiation Oncology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
6Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
7Institute of Genetic Science, Yonsei University College of Medicine, Seodaemun-gu, Seoul 03722, Republic of Korea
†Contributed equally to this work
*Shared last authorship
Sun-Ho Lee, Jangho Lee and Jaewon Oh Contributed equally to this work.
Seung-Hyun Lee and Hyo-Kyoung Choi Shared last authorship
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 (DCM) 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 signaling, 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.
Conclusions: 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.
논문정보
- Research article
- 2024년 05월 (BRIC 등록일 2024-05-13)
- 국내 연구진
- 의약학 > 분자세포의학
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