The ototoxic drug cisplatin localises to stress granules altering their dynamics and composition.
The ototoxic drug cisplatin localises to stress granules altering their dynamics and composition.
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DOI：
10.1242/jcs.260590
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发表时间：
2023-07-15
影响因子：
4
通讯作者：
Dawson, Sally J.
中科院分区：
文献类型：
--
作者：
Martin, Jack L.;Terry, Stephen J.;Gale, Jonathan E.;Dawson, Sally J.
顺铂是一种有效的铂基化疗药物，有几种副作用，包括耳毒性。耳蜗细胞增殖率低，但对顺铂高度敏感。我们假设顺铂耳毒性可能是由顺铂-蛋白质相互作用而不是顺铂- dna相互作用引起的。两种已知的顺铂结合蛋白参与应激颗粒（SG）反应。SGs是一种促进生存的机制，涉及应激过程中瞬态核糖核蛋白复合物的形成。我们研究了顺铂对耳蜗和视网膜色素上皮细胞系SG动力学和组成的影响。与亚砷酸盐诱导的SGs相比，顺铂诱导的SGs在大小和数量上明显减少，并且在24小时恢复后持续存在。此外，顺铂预处理的细胞不能对随后的亚砷酸盐应激形成典型的SG反应。顺铂诱导的SGs明显减少了eIF4G和RACK1、DDX3X蛋白的分离。德克萨斯红结合顺铂的活细胞成像显示其定位于SGs并保留至少24小时。我们发现，顺铂诱导的耳蜗组装受损，成分改变，并且持续存在，这为顺铂诱导的耳蜗反应受损的另一种机制提供了证据。摘要：顺铂引起持续和异常的应激颗粒形成，这可能导致其耳毒性，这是癌症化疗的常见副作用。
Cisplatin is an effective platinum-based chemotherapeutic with several side effects, including ototoxicity. Cochlear cells have low rates of proliferation yet are highly susceptible to cisplatin. We hypothesised that cisplatin ototoxicity might be caused by cisplatin–protein interactions rather than cisplatin–DNA interactions. Two known cisplatin-binding proteins are involved in the stress granule (SG) response. SGs are a pro-survival mechanism involving formation of transient ribonucleoprotein complexes during stress. We examined the effects of cisplatin on SG dynamics and composition in cell lines derived from the cochlea and retinal pigment epithelium. Cisplatin-induced SGs are significantly diminished in size and quantity compared to arsenite-induced SGs and are persistent after 24 h recovery. Additionally, cisplatin pre-treated cells were unable to form a typical SG response to subsequent arsenite stress. Cisplatin-induced SGs had significant reductions in the sequestration of eIF4G and the proteins RACK1 and DDX3X. Live-cell imaging of Texas Red-conjugated cisplatin revealed its localisation to SGs and retention for at least 24 h. We show cisplatin-induced SGs have impaired assembly, altered composition and are persistent, providing evidence of an alternate mechanism for cisplatin-induced ototoxicity via an impaired SG response. Summary: Cisplatin causes persistent and aberrant stress granule formation which might contribute to its ototoxicity, a common side effect of chemotherapy treatment for cancer.
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影响因子：
5.8
作者：
Reineke LC;Neilson JR
通讯作者：
Neilson JR
影响因子：
4
作者：
Reineke, Lucas C.;Cheema, Shebna A.;Neilson, Joel R.
通讯作者：
Neilson, Joel R.
影响因子：
5.3
作者：
Kim, WJ;Back, SH;Jang, SK
通讯作者：
Jang, SK
DOI：
10.1016/j.biopha.2021.112382
发表时间：
2022-01
期刊：
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
影响因子：
--
作者：
Pietras P;Aulas A;Fay MM;Leśniczak-Staszak M;Sowiński M;Lyons SM;Szaflarski W;Ivanov P
通讯作者：
Ivanov P
影响因子：
64.5
作者：
Buchan, J. Ross;Kolaitis, Regina-Maria;Parker, Roy
通讯作者：
Parker, Roy