Enhancing autophagy by down-regulating GSK-3β alleviates cisplatin-induced ototoxicity in vivo and in vitro
Enhancing autophagy by down-regulating GSK-3β alleviates cisplatin-induced ototoxicity in vivo and in vitro
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DOI：
10.1016/j.toxlet.2019.05.025
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发表时间：
2019-10-01
影响因子：
3.5
通讯作者：
Xiao, Hongjun
中科院分区：
文献类型：
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作者：
Liu, Tianyi;Zong, Shimin;Xiao, Hongjun
既往研究报道选择性GSK-3 β抑制剂或上调自噬均能减轻顺铂所致的耳毒性。其他研究表明GSK-3 β的活性与自噬水平密切相关。本研究的目的是初步探讨自噬在GSK-3 β抑制剂减轻顺铂耳毒性中的作用。我们观察了GSK-3 β抑制剂在顺铂诱导的耳毒性大鼠模型中诱导的外毛细胞（OHC）自噬变化。此外，在体外实验中使用自噬抑制剂3-MA，观察自噬抑制对GSK-3 β失活引起的细胞保护作用的影响。推测自噬、GSK-3 β与细胞损伤之间的关系。GSK-3 β的负调控显著增强自噬，减轻顺铂诱导的听力损失、体内OHC死亡和体外细胞凋亡。自噬抑制剂3-MA逆转了GSK-3 β负调节的保护作用。这些结果表明，增强自噬可能是GSK-3 β抑制在体内和体外减轻顺铂诱导的耳毒性中的关键下游效应。
Previous study reported that either selective GSK-3 beta inhibitor or up-regulating autophagy can alleviate cisplatin-induced ototoxicity. Other studies indicate that the activity of GSK-3 beta is closely associated with the autophagy level. The purpose of this study is to primarily explore the role of autophagy in the alleviation effect of GSK-3 beta inhibition on cisplatin-induced ototoxicity in vivo and in vitro. We observed the autophagy changes induced by GSK-3 beta inhibitor in outer hair cells (OHCs) in a cisplatin-induced ototoxicity rat model. In addition, autophagy inhibitor 3-MA was used in vitro experiments to observe the influence of autophagy inhibition on the cell protection effect due to GSK-3 beta inactivation. The relationship among autophagy, GSK-3 beta and cell damage were inferred. Negative regulation of GSK-3 beta significantly enhanced autophagy and alleviated cisplatin-induced hearing loss, OHC death in vivo and apoptosis in vitro. The autophagy inhibitor 3-MA inverted the protective effect of negative regulation of GSK-3 beta. These results indicated that enhancing autophagy may be a key downstream effect of GSK-3 beta inhibition in the alleviation of cisplatin-induced ototoxicity both in vivo and in vitro.