Department of Otolaryngology-Head and Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai 200233, China; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai 200233, China.
Department of Otolaryngology-Head and Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai 200233, China; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai 200233, China; Department of Otolaryngology-Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, China.
Biochem Pharmacol. 2022 Mar;197:114904. doi: 10.1016/j.bcp.2021.114904. Epub 2021 Dec 28.
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. Unfortunately, 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. Additionally, trehalose significantly enhanced autophagy levels in HCs, and inhibiting autophagy with 3-methyladenine (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 calcineurin 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.
顺铂是一种广泛用于治疗各种肿瘤的化疗药物，但它的副作用限制了它的应用。耳毒性是顺铂的主要不良反应之一，会导致不可逆转的感觉神经性听力损失。不幸的是，目前还没有有效的方法来预防这种损伤。自噬在各种疾病模型中表现出有益的作用。然而，自噬在顺铂诱导的耳毒性中的作用尚未得到充分阐明。在这项研究中，我们旨在研究新型自噬激活剂海藻糖是否可以预防顺铂诱导的听觉细胞系 HEI-OC1 和小鼠耳蜗外植体的损伤，并进一步探讨其机制。我们的数据表明，海藻糖通过抑制细胞凋亡、减轻氧化应激和挽救线粒体功能来减轻顺铂诱导的毛细胞 (HC) 损伤。此外，海藻糖显著增加了 HC 中的自噬水平，而用 3-甲基腺嘌呤 (3-MA) 抑制自噬则消除了这些保护作用。在机制上，我们表明，海藻糖的作用归因于转录因子 EB (TFEB) 的核易位增加，这种作用可以通过 TFEB 的过表达模拟，并可以通过 TFEB 基因沉默或钙调神经磷酸酶抑制剂环孢素 A (CsA) 抑制。总之，我们的研究结果表明，海藻糖和自噬在保护顺铂诱导的耳毒性方面发挥作用，并且通过 TFEB 介导的自噬的药理学增强可能是治疗耳蜗 HC 和 HEI-OC1 细胞中顺铂损伤的一种潜在方法。
