Proteasome inhibitors induce auditory hair cell death through peroxisome dysfunction
Proteasome inhibitors induce auditory hair cell death through peroxisome dysfunction
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DOI：
10.1016/j.bbrc.2014.11.070
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发表时间：
2015-01-02
影响因子：
3.1
通讯作者：
Park, Raekil
中科院分区：
文献类型：
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作者：
Lee, Joon No;Kim, Seul-Gi;Park, Raekil
尽管硼替佐米是一种蛋白酶体抑制剂，是一种用于治疗多发性骨髓瘤（MM）和其他淋巴瘤细胞的强效化疗药物，但最近的临床报告表明，蛋白酶体抑制剂治疗可能与严重的双侧听力损失相关。我们在此研究蛋白酶体抑制剂对听毛细胞的不良影响。蛋白酶体抑制剂的处理破坏毛细胞的静纤毛束，导致Corti器官外植体中静纤毛的混乱。由于蛋白酶体活性可能对过氧化物酶体的生物发生和功能具有潜在的重要性，我们测试了蛋白酶体活性是否是维持功能性过氧化物酶体所必需的。我们的研究结果表明，蛋白酶体抑制剂的治疗显着降低过氧化物酶体的数量和过氧化物酶体蛋白，如PMP 70和过氧化氢酶的表达。此外，我们还发现蛋白酶体抑制剂损害了PTS 1-过氧化物酶体基质蛋白的输入途径。总之，我们的研究结果支持最近的临床报告听力损失与蛋白酶体抑制。从机制上讲，过氧化物酶体功能障碍可能导致毛细胞损伤和听力损失，以响应蛋白酶体抑制剂的治疗。(C)2014爱思唯尔公司All rights reserved.
Even though bortezomib, a proteasome inhibitor, is a powerful chemotherapeutic agent used to treat multiple myeloma (MM) and other lymphoma cells, recent clinical reports suggest that the proteasome inhibitor therapy may be associated with severe bilateral hearing loss. We herein investigated the adverse effect of proteasome inhibitor on auditory hair cells. Treatment of a proteasome inhibitor destroys stereocilia bundles of hair cells resulting in the disarray of stereocilia in the organ of Corti explants. Since proteasome activity may be potentially important for biogenesis and function of the peroxisome, we tested whether proteasome activity is necessary for maintaining functional peroxisomes. Our results showed that treatment of a proteasome inhibitor significantly decreases both the number of peroxisomes and expression of peroxisomal proteins such as PMP70 and Catalase. In addition, we also found that proteasome inhibitor impairs the import pathway of PTS1-peroxisome matrix proteins. Taken together, our findings support recent clinical reports of hearing loss associated with proteasome inhibition. Mechanistically, peroxisome dysfunction may contribute to hair cell damage and hearing loss in response to the treatment of a proteasome inhibitor. (C) 2014 Elsevier Inc. All rights reserved.