目的:阿霉素(DOX)是一种广泛使用的蒽环类抗癌药;然而,其对心脏的不可逆影响可导致癌症治疗后DOX诱导的心脏毒性(DICT)。不幸的是,DICT的病理生理学尚未完全阐明,并且没有有效的预防或治疗策略。在这次调查中,探讨了转导β样蛋白1(TBL1)在DICT的发展和调节中的新作用。
结果:我们观察到诊断为扩张型心肌病(DCM)和DICT的患者移植心脏组织中TBL1蛋白表达水平的降低以及裂解事件。揭示了DOX在半胱天冬酶-3优选位点-D125、D136和D215选择性诱导TBL1切割。有趣的是,未切割的TBL1突变体(TBL1uclv)变体的过表达减少了细胞凋亡,有效预防DOX诱导的细胞死亡。我们证实切割的TBL1不能与β-连环蛋白形成复合物。因此,Wnt记者活动,和Wnt靶基因表达共同表明Wnt/β-catenin信号的减少,导致DICT进步。此外,切割的TBL1触发了DOX诱导的异常电生理特征并破坏了钙稳态。然而,这些效应在过表达TBL1uclv的人诱导多能干细胞来源的心肌细胞中得到改善.最后,在DICT小鼠模型中,TBL1uclv过表达抑制DICT诱导的心肌收缩力降低和胶原积累,最终保护心肌细胞免受细胞死亡。
结论:我们的发现表明,抑制TBL1裂解不仅减轻了细胞凋亡,而且增强了心肌细胞功能,即使在DOX管理的背景下。因此,这项研究的结果表明,抑制TBL1裂解可能是改善DICT的新策略。
OBJECTIVE: 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.
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.
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.