Von Hippel-Lindau - Coupled and Transcription-Coupled Nucleotide Excision Repair - Dependent Degradation of RNA Polymerase 11 in Response to Trabectendin
Von Hippel-Lindau - Coupled and Transcription-Coupled Nucleotide Excision Repair - Dependent Degradation of RNA Polymerase 11 in Response to Trabectendin
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DOI：
10.1158/1078-0432.ccr-08-0730
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发表时间：
2008-10-15
影响因子：
11.5
通讯作者：
Pommier, Yves
中科院分区：
文献类型：
--
作者：
Aune, Gregory J.;Takagi, Kazutaka;Pommier, Yves
目的：Ecteinascidin 743 （Et743; trabectedin,Yondelis）最近在欧洲被批准用于治疗软组织肉瘤，并正在进行其他实体肿瘤的临床试验。Et743选择性地靶向精通TC-NER的细胞，这使其与其他DNA烷基化剂区别开来。在本研究中，我们检测了Et743对RNA Pol II的影响。实验设计和结果：我们报道了Et743诱导多种癌细胞系和正常成纤维细胞中转录Pol II的快速和大量降解。蛋白酶体抑制剂MG132消除了Pol II的降解，并依赖于TC-NER。Cockayne综合征（CS）细胞和着色性干皮病（XP）细胞（XPD， XPA， XPG和XPF）在Pol II降解方面存在缺陷，而XPC细胞的缺陷仅限于非转录区域的全局基因组NER，它们对Pol II降解是熟练的。CSB和XPD细胞的互补恢复了Pol II的降解。我们还表明，VHL复合物缺陷的细胞在Pol II降解中存在缺陷，这些细胞的互补恢复了Pol II的降解。此外，VHL缺乏使细胞抵抗et743诱导的细胞死亡，其效果与TC-NER缺乏相似。结论：TC-NER诱导的和vhl介导的Pol II降解均在Et743杀伤细胞中起作用。
Purpose: Ecteinascidin 743 (Et743; trabectedin,Yondelis) has recently been approved in Europe for the treatment of soft tissue sarcomas and is undergoing clinical trials for other solid tumors. Et743 selectively targets cells proficient for TC-NER, which sets it apart from other DNA alkylating agents. In the present study, we examined the effects of Et743 on RNA Pol II.Experimental Design and Results: We report that Et743 induces the rapid and massive degradation of transcribing Pol II in various cancer cell lines and normal fibroblasts. Pol II degradation was abrogated by the proteasome inhibitor MG132 and was dependent on TC-NER. Cockayne syndrome (CS) cells and xeroderma pigmentosum (XP) cells (XPD, XPA, XPG, and XPF) were defective in Pol II degradation, whereas XPC cells whose defect is limited to global genome NER in nontranscribing regions were proficient for Pol II degradation. Complementation of the CSB and XPD cells restored Pol II degradation.We also show that cells defective for the VHL complex were defective in Pol II degradation and that complementation of those cells restores Pol II degradation. Moreover, VHL deficiency rendered cells resistant to Et743-induced cell death, a similar effect to that of TC-NER deficiency.Conclusion: These results suggest that both TC-NER - induced and VHL-mediated Pol II degradation play a role in cell killing by Et743.