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  3. 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

  • Biochem Pharmacol. 2022 Mar;197:114904. doi: 10.1016/j.bcp.2021.114904.
Zhuangzhuang Li 1,  Qingxiu Yao 1,  Yuxin Tian 2,  Yumeng Jiang 1,  Maoxiang Xu 1,  Hui Wang 3,  Yuanping Xiong 4,  Jia Fang 5,  Wen Lu 6,  Dongzhen Yu 7,  Haibo Shi 1
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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 Otorhinolaryngology-Head and Neck Surgery, ENT Institute and Otorhinolaryngology, Department of Affiliated Eye and ENT Hospital, Fudan University, China.
  • 4 Department of Otolaryngology Head and Neck Surgery, First Affiliated Hospital of Nanchang University, Nanchang, China.
  • 5 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. Electronic address: fangjia2008@sjtu.edu.cn.
  • 6 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. Electronic address: luwenlanmo@sjtu.edu.cn.
  • 7 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. Electronic address: 7250012023@shsmu.edu.cn.
PMID: 34971589 DOI: 10.1016/j.bcp.2021.114904
Abstract

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.

Keywords

Autophagy; Cisplatin; Ototoxicity; Transcription factor EB (TFEB); Trehalose.

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