Activation of Wnt/β-catenin signaling to increase B lymphoma Moloney murine leukemia virus insertion region 1 by lithium chloride attenuates the toxicity of cisplatin in the HEI-OC1 auditory cells.

Abstract

Cisplatin is widely used in anti-tumor therapy, but the ototoxicity caused by high-dose cisplatin often limits its efficacy, and the specific mechanism of cisplatin-induced cochlear damage is still not perfect. The Wnt/β-catenin signaling pathway is closely related to aging, embryonic development, and apoptosis. Meanwhile, B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1) plays a certain role in the evolution and development of the inner ear and the occurrence and development of inner ear-related diseases. Our study intends to explore the role and specific mechanism of the Wnt/β-catenin signaling pathway and BMI1 in improving cisplatin ototoxicity. The appropriate experimental concentrations for each drug were selected by CCK-8 cell proliferation assay and Western Blot to detect apoptosis. The lentivirus transfection of HEI-OC1 cochlear hair cells was used to overexpress BMI1. Western Blot, qPCR, and immunofluorescence detected the activation of each component of BMI1 and Wnt/β-catenin signaling pathway in each experimental model. Wnt/β-catenin signaling pathway and BMI1 are jointly involved in cisplatin-induced cell injury. Low lithium chloride (LiCl) concentrations activated the Wnt/β-catenin pathway, increased BMI1 expression, and reduced cisplatin-induced hair cell injury. In contrast, overexpression of BMI1 inhibited the Wnt/β-catenin pathway and reduced hair cell injury. Meanwhile, the increased cisplatin-induced damage to hair cells by inhibiting BMI1 could not be rescued by LiCl. In conclusion, LiCl can ameliorate cisplatin ototoxicity by elevating BMI1 expression through activation of the Wnt/β-catenin pathway. Overexpression of BMI1 inhibits the Wnt/β-catenin pathway and reduces cisplatin-induced hair cell damage.