ARC protects cochlear hair cells from neomycin-induced ototoxicity via the Ras/JNK signaling pathway

Xiaoyu Yu; Hanbing Gao; Jie Zhang; Qiaojun Fang; Wenjie Kang; Haiqiong Shang; Xiangyu Lou; Ming Guan

doi:10.1016/j.toxlet.2024.12.005

ARC protects cochlear hair cells from neomycin-induced ototoxicity via the Ras/JNK signaling pathway

Toxicol Lett. 2024 Dec 10:403:111-119. doi: 10.1016/j.toxlet.2024.12.005. Online ahead of print.

Authors

Xiaoyu Yu¹, Hanbing Gao², Jie Zhang³, Qiaojun Fang⁴, Wenjie Kang², Haiqiong Shang¹, Xiangyu Lou¹, Ming Guan⁵

Affiliations

¹ Department of Otolaryngology, Hangzhou First People's Hospital, School of Medicine, Affiliated to Westlake University, Hangzhou, Zhejiang, China; The Fourth school of Medicine Affiliated to Zhejiang Chinese Medical University, Hangzhou, China.
² The Fourth school of Medicine Affiliated to Zhejiang Chinese Medical University, Hangzhou, China.
³ Department of Pediatrics, Hangzhou Children's Hospital, Hangzhou, Zhejiang, China.
⁴ Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
⁵ Department of Otolaryngology, Hangzhou First People's Hospital, School of Medicine, Affiliated to Westlake University, Hangzhou, Zhejiang, China; The Fourth school of Medicine Affiliated to Zhejiang Chinese Medical University, Hangzhou, China. Electronic address: guanming2000@163.com.

PMID: 39667535
DOI: 10.1016/j.toxlet.2024.12.005

Abstract

The present study was designed to investigate the role and mechanism of the Apoptosis repressor with caspase recruitment domain (ARC) in protecting the neomycin-induced hair cell damage. HEI-OC1 cells and basilar membrane culture were applied to determine the effect of ARC. Plasmid transfection was used to regulate the ARC or Ras expression. We have found the ARC overexpression in HEI-OC1 cells can increase the cell viability and decrease cell apoptosis after neomycin injury. The cleaved caspase 3 was reduced in ARC overexpression group after neomycin treatment. The p-CREB expression was increased in ARC overexpression group, while the p-c-Jun expression was decreased after neomycin incubation. In HEI-OC1 cells and basilar membranes, JNK and Ras inhibitions both can reduce ARC expression, and Ras overexpression can increase the ARC expression. This study indicates that ARC can protect the hair cells from neomycin-induced apoptosis through Ras/JNK signaling pathway. Our findings provide new insights in preventing cochlear HC death after drug-induced ototoxicity.

Keywords: ARC; Hair cells; MAPKs; Neomycin; Ototoxicity; Ras.