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

作者：Sun‐Ho Lee, Jangho Lee, Jangho Lee, Jaewon Oh, Jin‐Taek Hwang, Hae‐Jeung Lee, Hwa Kyung Byun, Hyeong-Jin Kim, David Suh, Ho‐Geun Yoon, Sahng Wook Park, Seok‐Min Kang, Chulan Kwon, Seung-Hyun Lee, Seung‐Hyun Lee, Hyo‐Kyoung Choi · 发表于：Cardiovascular Research · 年份：2024 · DOI：10.1093/cvr/cvae098 · 被引用次数：4 · 研究领域：Chemotherapy-induced cardiotoxicity and mitigation、Cell death mechanisms and regulation、Cardiac electrophysiology and arrhythmias

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 card...