Cisplatin is a widely used chemotherapeutic drug for treating various solid tumors. Ototoxicity is a major dose-limiting side effect of cisplatin, which causes progressive and irreversible sensorineural hearing loss. Here, we examined the protective effects of glucose-related protein (GRP) 78 and 94, also identified as endoplasmic reticulum (ER) chaperone proteins, on cisplatin-induced ototoxicity. Treating murine auditory cells (HEI-OC1) with 25 μM cisplatin for 24 h increased cell death resulting from excessive intracellular reactive oxygen species (ROS) accumulation and caspase-involved apoptotic signaling pathway activation with subsequent DNA fragmentation. GRP78 and GRP94 expression was increased in cells treated with 3 nM thapsigargin or 0.1 μg/mL tunicamycin for 24 h, referred to as mild ER stress condition. This condition, prior to cisplatin exposure, attenuated cisplatin-induced ototoxicity. The involvement of GRP78 and GRP94 induction was demonstrated by the knockdown of GRP78 or GRP94 expression using small interfering RNAs, which abolished the protective effect of mild ER stress condition on cisplatin-induced cytotoxicity. These results indicated that GRP78 and GRP94 induction plays a protective role in remediating cisplatin-ototoxicity.

中文翻译：

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葡萄糖相关蛋白78和94对顺铂介导的耳毒性的保护作用。

顺铂是用于治疗各种实体瘤的广泛使用的化学治疗药物。耳毒性是顺铂的主要剂量限制副作用，可引起进行性和不可逆的感觉神经性听力损失。在这里，我们检查了葡萄糖相关蛋白（GRP）78和94（也被确定为内质网（ER）伴侣蛋白）对顺铂诱导的耳毒性的保护作用。用25μM顺铂处理鼠听觉细胞（HEI-OC1）24小时会增加细胞死亡，这是由于细胞内活性氧（ROS）过多积累和caspase参与的凋亡信号通路激活以及随后的DNA片段化所致。在用3 nM毒胡萝卜素或0.1μg/ mL衣霉素处理24小时的细胞中，GRP78和GRP94的表达增加，称为轻度ER应激条件。这种情况 顺铂暴露前，顺铂引起的耳毒性减弱。GRP78和GRP94诱导的参与通过使用小的干扰RNA敲低GRP78或GRP94表达来证明，这消除了轻度ER应激条件对顺铂诱导的细胞毒性的保护作用。这些结果表明，GRP78和GRP94的诱导在补救顺铂耳毒性中起保护作用。