Proteomic analysis of the balance between survival and cell death responses in cisplatin-mediated ototoxicity
Proteomic analysis of the balance between survival and cell death responses in cisplatin-mediated ototoxicity
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DOI：
10.1021/pr8002479
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发表时间：
2008-08-01
影响因子：
4.4
通讯作者：
Coling, Donald E.
中科院分区：
文献类型：
--
作者：
Jamesdaniel, Samson;Ding, Dalian;Coling, Donald E.
顺铂是一种广泛使用的抗癌药物，它优先损害内耳的外毛细胞（OHCs）。在这项研究中，抗体芯片被用于鉴定顺铂诱导的大鼠耳蜗蛋白表达的早期变化。顺铂治疗（12 mg/kg） 2天后，仅检测到听力阈值的微小变化（4-34 dB升高）。耳声发射测量的OHC功能轻微下降（10 dB），很少或没有观察到受体细胞损失。然而，顺铂诱导19种参与细胞凋亡、细胞存活或细胞周期进展的蛋白的表达发生巨大变化。其中15种蛋白质是内耳研究中的新发现。免疫印迹证实促存活激活转录因子2 （ATF2）、促凋亡丝氨酸-苏氨酸蛋白激酶、受体相互作用蛋白和功能未知的70/75 kDa含硝基酪氨酸双偶体水平升高。抗硝基酪氨酸抗体将这些氧化损伤的蛋白定位于OHCs的立体纤毛、Hensen细胞的高尔基中心体区域、外柱细胞的细胞核和支配OHCs的隧道交叉纤维。蛋白质组学分析的结果反映了在观察到显著的功能或解剖损失之前耳毒性和细胞存活反应的开始。
Cisplatin, a widely used anticancer drug, preferentially damages outer hair cells (OHCs) of the inner ear. In this study, an antibody microarray was used to identify early changes in protein expression in the rat cochlea induced by cisplatin. Only small changes in hearing thresholds (4-34 dB elevation) were detected two days after cisplatin treatment (12 mg/kg). OHC function, measured by otoacoustic emissions, was slightly depressed (10 dB), and little or no receptor cell loss was observed. However, cisplatin induced large changes in the expression of 19 proteins involved in apoptosis, cell survival, or progression through the cell cycle. Fifteen of the proteins are novel to the study of the inner ear. Immunoblotting confirmed increases in the levels of the pro-survival activating transcription factor 2 (ATF2), of pro-apoptotic serine-threonine protein kinase, receptor interacting protein, and a 70/75 kDa nitrotyrosine bearing doublet of unknown function. Anti-nitrotyrosine antibodies localized these oxidatively damaged proteins to the stereocilia of OHCs, the Golgi-centrosome region of Hensen's cells, nuclei of outer pillar cells, and tunnel crossing fibers innervating OHCs. The results of this proteomic analysis reflect the commencement of ototoxic and cell survival responses before the observation of a significant functional or anatomical loss.