Trehalose protects against cisplatin-induced cochlear hair cell damage by activating TFEB-mediated autophagy
Trehalose protects against cisplatin-induced cochlear hair cell damage by activating TFEB-mediated autophagy
复制标题
海藻糖通过激活 TFEB 介导的自噬来防止顺铂诱导的耳蜗毛细胞损伤。
DOI：
10.1016/j.bcp.2021.114904
复制
发表时间：
2022-01-04
影响因子：
5.8
通讯作者：
Shi, Haibo
中科院分区：
文献类型：
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作者：
Li, Zhuangzhuang;Yao, Qingxiu;Shi, Haibo
顺铂是一种广泛应用于各种肿瘤治疗的化疗药物，但其副作用限制了其应用。耳毒性是顺铂的主要不良反应，可导致不可逆的感音神经性听力损失。不幸的是，没有有效的方法来防止这种损害。自噬已被证明在各种疾病模型中发挥有益作用。然而，自噬在顺铂诱导的耳毒性中的作用尚未得到很好的阐明。本研究旨在探讨新型自噬激活剂海藻糖是否能预防顺铂诱导的听觉细胞系HEI-OC 1和小鼠耳蜗移植物损伤，并进一步探讨其机制。我们的数据表明，海藻糖减轻顺铂诱导的毛细胞（HC）损伤，抑制细胞凋亡，减轻氧化应激和挽救线粒体功能障碍。此外，海藻糖显著增强HC中的自噬水平，并且用3-甲基腺嘌呤（3-MA）抑制自噬可消除这些保护作用。从机制上讲，我们发现海藻糖的作用是由于转录因子EB（TFEB）的核转位增加，这种作用可以通过TFEB过表达来模拟，并通过TFEB基因沉默或用环孢菌素A（CsA）（一种钙神经元抑制剂）治疗来抑制。综上所述，我们的研究结果表明，海藻糖和自噬在预防顺铂诱导的耳毒性中发挥作用，并且TFEB介导的自噬的药理学增强是耳蜗HC和HEI-OC 1细胞中顺铂诱导的损伤的潜在治疗。
Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors, but its side effects limit its application. Ototoxicity, a major adverse effect of cisplatin, causes irreversible sensorineural hearing loss. Un-fortunately, there are no effective approaches to protect against this damage. Autophagy has been shown to exert beneficial effects in various diseases models. However, the role of autophagy in cisplatin-induced ototoxicity has been not well elucidated. In this study, we aimed to investigate whether the novel autophagy activator trehalose could prevent cisplatin-induced damage in the auditory cell line HEI-OC1 and mouse cochlear explants and to further explore its mechanisms. Our data demonstrated that trehalose alleviated cisplatin-induced hair cell (HC) damage by inhibiting apoptosis, attenuating oxidative stress and rescuing mitochondrial dysfunction. Addi-tionally, trehalose significantly enhanced autophagy levels in HCs, and inhibiting autophagy with 3-methylade-nine (3-MA) abolished these protective effects. Mechanistically, we showed that the effect of trehalose was attributed to increased nuclear translocation of transcription factor EB (TFEB), and this effect could be mimicked by TFEB overexpression and inhibited by TFEB gene silencing or treatment with cyclosporin A (CsA), a calci-neurin inhibitor. Taken together, our findings suggest that trehalose and autophagy play a role in protecting against cisplatin-induced ototoxicity and that pharmacological enhancement of TFEB-mediated autophagy is a potential treatment for cisplatin-induced damage in cochlear HCs and HEI-OC1 cells.