RNA结合蛋白作为氯福克酚药靶的机制初探

基础医学与临床 ›› 2020, Vol. 40 ›› Issue (5): 621-626.

RNA结合蛋白作为氯福克酚药靶的机制初探

张美莲¹, 王志星¹, 胡艳¹, 冉坤念¹, 韩为^1*, 彭小忠^1,2*

1.中国医学科学院基础医学研究所北京协和医学院基础学院医学分子生物学国家重点实验室生物化学与分子生物学系医学灵长类研究中心神经科学中心, 北京 100005;
2.中国医学科学院医学生物学研究所,云南昆明 650118

收稿日期:2020-01-14 修回日期:2020-03-18 出版日期:2020-05-05 发布日期:2020-04-30
通讯作者: *pengxiaozhong@pumc.edu.cn; hanwei2012@ibms.pumc.edu.cn
基金资助:
国家自然科学基金(31671316);北京市科技新星计划(Z191100001119137);中国医学科学院创新工程项目(2016-I2M-1-001,2017-I2M-2-004);医科院基科费(2018RC310014)

Preliminary study on the mechanism of RNA-binding protein as a drug target of clofoctol

ZHANG Mei-lian¹, WANG Zhi-xing¹, HU Yan¹, RAN Kun-nian¹, HAN Wei^1*, PENG Xiao-zhong^1,2*

1. State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Medical Primate Research Center, Neuroscience Center, Institute of Basic Medical Sciences CAMS, School of Basic Medicine PUMC, Beijing 100005;
2. Institute of Medical Biology, Chinese Academy of Medical Sciences, Kunming 650118, China

Received:2020-01-14 Revised:2020-03-18 Online:2020-05-05 Published:2020-04-30
Contact: *pengxiaozhong@pumc.edu.cn; hanwei2012@ibms.pumc.edu.cn

摘要/Abstract

摘要： 目的探索氯福克酚靶向RNA结合蛋白的抗胶质瘤机制。方法 Biotin pull-down实验检测RNA结合蛋白N-ras上游蛋白(UNR)与靶基因Krüppel样因子13(KLF13 )mRNA各片段的结合,以及氯福克酚对UNR与下游靶基因KLF13 mRNA片段结合能力的影响;氯福克酚靶点稳定性的药物亲和反应(DARTS)样品质谱检测结果与转录组芯片分析相结合,筛选其他RNA结合蛋白作用靶点,并对其他下游靶基因进行预测分析。结果氯福克酚可以增强UNR与KLF13 mRNA片段的结合;氯福克酚还可与其他RNA结合蛋白相互作用,参与mTOR信号通路以及由肿瘤坏死因子相关凋亡诱导配体(TRAIL)激活的凋亡信号通路。结果氯福克酚可通过作用于RNA结合蛋白而起到抗胶质瘤的效果。

关键词: 氯福克酚, 胶质瘤, UNR, KLF13 mRNA, RNA结合蛋白

Abstract: Objective To explore the molecular mechanism of anti-glioma by clofoctol targeting on RNA-binding proteins. Methods Biotin pull-down experiments were used to detect the binding of RNA-binding protein UNR (upstream of N-ras) to the target gene Krüppel-like factor 13(KLF13) mRNA fragments, and the effect of clofoctol on the binding to UNR to KLF13 mRNA fragments; The results of clofoctol DARTS sample's mass spectrometry combined with transcriptome chip analysis were used to screen other RNA-binding protein targets and to predict other downstream target genes. Results Clofoctol enhanced the interaction between UNR and the fragment of KLF13 mRNA; Clofoctol also acted on other RNA-binding proteins, and functioned in mTOR signaling pathway and TNF-related apoptosis-inducing ligand (TRAIL)-activated apoptotic signaling pathway. Conclusions Clofoctol can resist gliomas by acting on RNA-binding proteins.

Key words: clofoctol, glioma, UNR, KLF13 mRNA, RNA-binding proteins

中图分类号:

张美莲, 王志星, 胡艳, 冉坤念, 韩为, 彭小忠. RNA结合蛋白作为氯福克酚药靶的机制初探[J]. 基础医学与临床, 2020, 40(5): 621-626.

ZHANG Mei-lian, WANG Zhi-xing, HU Yan, RAN Kun-nian, HAN Wei, PENG Xiao-zhong. Preliminary study on the mechanism of RNA-binding protein as a drug target of clofoctol[J]. Basic & Clinical Medicine, 2020, 40(5): 621-626.

参考文献

[1]Meir EGV, Hadjipanayis CG, Norden AD, et al. Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma[J]. CA Cancer J Clin, 2010, 60:166-193.
[2]Cheng L, Bao S, Rich JN. Potential therapeutic implications of cancer stem cells in glioblastoma[J]. Biochem Pharmacol, 2010, 80:654-665.
[3]Barcelos LS, Duplaa C, Krankel N, et al. Human CD133⁺ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling[J]. Circ Res, 2009, 104: 1095-1102.
[4]Bao S, Wu Q, Roger E, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response[J]. Nature, 2006, 444: 756-760.
[5]Hu Y, Zhang ML, Tian NY, et al. The antibiotic clofoctol suppresses glioma stem cell proliferation by activating KLF13[J]. J Clin Invest, 2019, 12:3072-3085.
[6]Liao JY, Yang B, Zhang YC, et al. EuRBPDB: a comprehensive resource for annotation, functional and oncological investigation of eukaryotic RNA binding proteins (RBPs)[J]. Nucleic Acids Res, 2019, 48:307-313.
[7]Wurth L, Papasaikas P, Olmeda D, et al. UNR/CSDE1 drives a post-transcriptional program to promote melanoma invasion and metastasis[J]. Cancer Cell, 2016, 30:694-707.
[8]Hattangadi SM, Martinezmorilla S, Patterson HC, et al. Histones to the cytosol: exportin 7 is essential for normal terminal erythroid nuclear maturation[J]. Blood, 2014, 124:1931-1940.
[9]Han W, Xin Z, Zhao Z, et al. RNA-binding protein PCBP2 modulates glioma growth by regulating FHL3[J]. J Clin Invest, 2013, 123:2103-2118.
[10]Tian NY, Qi YJ, Hu Y, et al. RNA-binding protein UNR promotes glioma cell migration and regulates the expression of ribosomal protein L9[J]. Chin Med Sci J, 2018, 33:143-151.
[11]Hong S. RNA binding protein as an emerging therapeutic target for cancer prevention and treatment[J]. J Cancer Prev, 2017, 22:203-210.

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