Inhibition of RNA polymerase III transcription by Triptolide attenuates colorectal tumorigenesis
Inhibition of RNA polymerase III transcription by Triptolide attenuates colorectal tumorigenesis
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雷公藤甲素抑制 RNA 聚合酶 III 转录可减弱结直肠肿瘤的发生
DOI：
10.1186/s13046-019-1232-x
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发表时间：
2019-05-23
影响因子：
11.3
通讯作者：
Gao, Xiangwei
中科院分区：
文献类型：
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作者：
Liang, Xia;Xie, Renxiang;Gao, Xiangwei
RNA聚合酶（Pol）III产物（包括tRNA和5S rRNA）在肿瘤细胞中的上调导致蛋白质合成和肿瘤形成的增强，使其成为癌症治疗的潜在靶点。在这项研究中，我们评估了雷公藤甲素和这种药物在结直肠tumorogenesis.MethodsThe影响的抑制Pol III转录的结直肠癌的发展进行了评估，在结直肠癌小鼠模型，三维类器官，和培养的细胞。用雷公藤内酯醇处理大肠癌细胞。通过实时定量聚合酶链反应（PCR）测量Pol III转录。TFIIIB的形成，一个多亚基的转录因子Pol III，确定通过染色质免疫沉淀（ChIP），免疫共沉淀（Co-IP），和荧光共振能量转移（FRET）。ResultsTriptolide减少肿瘤数量和肿瘤大小在腺瘤性息肉病大肠杆菌（APC）突变（Apc Min/+）小鼠以及AOM/DSS诱导的小鼠。此外，雷公藤内酯醇有效地抑制大肠癌细胞增殖，集落形成，和类器官生长在体外，这是与减少Pol III靶基因。从机制上讲，雷公藤内酯醇治疗阻断TBP/Brf 1相互作用，导致减少形成TFIIIB在启动子的tRNA和5S rRNA.ConclusionsTogether，我们的数据表明，抑制Pol III转录与现有的药物，如雷公藤内酯醇提供了一个新的途径，开发新的治疗结直肠癌。
BackgroundUpregulation of RNA polymerase (Pol) III products, including tRNAs and 5S rRNA, in tumor cells leads to enhanced protein synthesis and tumor formation, making it a potential target for cancer treatment. In this study, we evaluated the inhibition of Pol III transcription by triptolide and the anti-cancer effect of this drug in colorectal tumorigenesis.MethodsThe effect of triptolide on colorectal cancer development was assessed in colorectal cancer mouse models, 3D organoids, and cultured cells. Colorectal cancer cells were treated with triptolide. Pol III transcription was measured by real-time quantitative polymerase chain reaction (PCR). The formation of TFIIIB, a multi-subunit transcription factor for Pol III, was determined by chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and fluorescence resonance energy transfer (FRET).ResultsTriptolide reduced both tumor number and tumor size in adenomatous polyposis coli (Apc) mutated (Apc Min/+) mice as well as AOM/DSS-induced mice. Moreover, triptolide effectively inhibited colorectal cancer cell proliferation, colony formation, and organoid growth in vitro, which was associated with decreased Pol III target genes. Mechanistically, triptolide treatment blocked TBP/Brf1interaction, leading to the reduced formation of TFIIIB at the promoters of tRNAs and 5S rRNA.ConclusionsTogether, our data suggest that inhibition of Pol III transcription with existing drugs such as triptolide provides a new avenue for developing novel therapies for colorectal cancer.