Downregulation of vimentin expression increased drug resistance in ovarian cancer cells.
Downregulation of vimentin expression increased drug resistance in ovarian cancer cells.
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波形蛋白表达下调增加卵巢癌细胞的耐药性
DOI：
10.18632/oncotarget.9970
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发表时间：
2016-07-19
期刊：
影响因子：
--
通讯作者：
Deng H
中科院分区：
文献类型：
--
作者：
Huo Y;Zheng Z;Chen Y;Wang Q;Zhang Z;Deng H
顺铂等铂类药物已被广泛应用于卵巢癌的治疗，但大多数患者获得耐药性，大大影响了药物的疗效。了解耐药机制对于寻找新的治疗方法具有重要意义。在本研究中，我们发现，波形蛋白的表达在卵巢癌耐药细胞系A2780-DR和HO-8910中下调，与它们各自的对照细胞相比。波形蛋白在A2780-DR细胞中的过表达显著增加了其对顺铂的敏感性，而波形蛋白在A2780、HO-8910-PM和HO-8910细胞中的敲低增加了对顺铂的耐药性，表明波形蛋白沉默增强了卵巢癌细胞对顺铂的耐药性。定量蛋白质组学分析鉴定了波形蛋白沉默的A2780细胞（A2780-VIM-KN）和对照细胞之间的95个差异表达蛋白，其中内吞蛋白的下调和外吞蛋白CHMP 2B和PDZK 1的上调被认为有助于波形蛋白敲低细胞中顺铂积累的减少。波形蛋白的沉默诱导肿瘤干细胞标志物的上调，并且A2780-DR和A2780-VIM-KN细胞在无血清培养条件下比对照细胞更容易形成球状体。我们的研究结果还表明，波形蛋白敲低增加了14-3-3介导的Cdc 25 C在细胞质中的保留，导致Cdk 1失活和延长的G2期阻滞，使细胞有更长的时间来修复顺铂损伤的DNA。总之，我们证明了波形蛋白沉默通过延长G2期阻滞和增加胞吐作用增强细胞对顺铂的抗性，表明波形蛋白是治疗耐药卵巢癌的潜在靶点。
Cisplatin and other platinum-based drugs have been widely used in the treatment of ovarian cancer, but most patients acquire the drug resistance that greatly compromises the efficacy of drugs. Understanding the mechanism of drug resistance is important for finding new therapeutic approaches. In the present study, we found that the expression of vimentin was downregulated in drug-resistant ovarian cancer cell lines A2780-DR and HO-8910 as compared to their respective control cells. Overexpression of vimentin in A2780-DR cells markedly increased their sensitivity to cisplatin, whereas knockdown of vimentin in A2780, HO-8910-PM and HO-8910 cells increased the resistance to cisplatin, demonstrating that vimentin silencing enhanced cisplatin resistance in ovarian cancer cells. Quantitative proteomic analysis identified 95 differentially expressed proteins between the vimentin silenced A2780 cells (A2780-VIM-KN) and the control cells, in which downregulation of endocytic proteins and the upregulation of exocytotic proteins CHMP2B and PDZK1 were proposed to contribute the decreased cisplatin accumulation in vimentin knockdown cells. Silencing of vimentin induced upregulation of cancer stem cell markers and both A2780-DR and A2780-VIM-KN cells were more facile to form spheroids than control cells under serum-free culture condition. Our results also revealed that vimentin knockdown increased the 14-3-3 mediated retention of Cdc25C in the cytoplasm, leading to inactivation of Cdk1 and the prolonged G2 phase arrest that allowed the longer period of time for cells to repair cisplatin-damaged DNA. Taken together, we demonstrated that vimentin silencing enhanced cells' resistance to cisplatin via prolonged G2 arrest and increased exocytosis, suggesting that vimentin is a potential target for treatment of drug resistant ovarian cancer.
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影响因子：
4.1
作者：
Kunz, C;Zurbriggen, K;Fleck, O
通讯作者：
Fleck, O
DOI：
10.1073/pnas.190030497
发表时间：
2000-09-12
影响因子：
11.1
作者：
Matsuoka, S;Rotman, G;Elledge, SJ
通讯作者：
Elledge, SJ
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影响因子：
7
作者：
Jin, Lixu;Huo, Yi;Deng, Haiteng
通讯作者：
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影响因子：
3.7
作者：
Kotula E;Faigle W;Berthault N;Dingli F;Loew D;Sun JS;Dutreix M;Quanz M
通讯作者：
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影响因子：
21.3
作者：
Engl, W.;Arasi, B.;Viasnoff, V.
通讯作者：
Viasnoff, V.