• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

阻断LRP16-PKR-NF-κB信号轴可使结肠癌细胞对DNA损伤性细胞毒性疗法敏感。

Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy.

作者信息

Li Xiaolei, Wu Zhiqiang, An Xiaojing, Mei Qian, Bai Miaomiao, Hanski Leena, Li Xiang, Ahola Tero, Han Weidong

机构信息

Department of Molecular Biology, Immunological and Bio-therapeutic, Institute of Basic Medicine, Chinese PLA General Hospital, Beijing, China.

Department of Pathology, Chinese PLA General Hospital, Beijing, China.

出版信息

Elife. 2017 Aug 18;6:e27301. doi: 10.7554/eLife.27301.

DOI:10.7554/eLife.27301
PMID:28820388
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5562444/
Abstract

Acquired therapeutic resistance by tumors is a substantial impediment to reducing the morbidity and mortality that are attributable to human malignancies. The mechanisms responsible for the dramatic shift between chemosensitivity and chemoresistance in colorectal carcinoma have not been defined. Here, we report that LRP16 selectively interacts and activates double-stranded RNA-dependent kinase (PKR), and also acts as scaffolds to assist the formation of a ternary complex of PKR and IKKβ, prolonging the polymers of ADP-ribose (PAR)-dependent nuclear factor kappa B (NF-κB) transactivation caused by DNA-damaging agents and confers acquired chemoresistance. We also identified a small molecule, MRS2578, which strikingly abrogated the binding of LRP16 to PKR and IKKβ, converting LRP16 into a death molecule and forestalling colon tumorigenesis. Inclusion of MRS2578 with etoposide, versus each drug alone, exhibited synergistic antitumor cytotoxicity in xenografts. Our combinatorial approach introduces a strategy to enhance the efficacy of genotoxicity therapies for the treatment of tumors.

摘要

肿瘤获得性治疗耐药性是降低人类恶性肿瘤所致发病率和死亡率的重大障碍。结直肠癌中化疗敏感性和化疗耐药性之间发生显著转变的机制尚未明确。在此，我们报告LRP16选择性地与双链RNA依赖性激酶（PKR）相互作用并激活它，还作为支架协助PKR和IKKβ形成三元复合物，延长由DNA损伤剂引起的ADP核糖（PAR）依赖性核因子κB（NF-κB）反式激活的聚合物，并赋予获得性化疗耐药性。我们还鉴定出一种小分子MRS2578，它显著消除了LRP16与PKR和IKKβ的结合，将LRP16转化为死亡分子并预防结肠肿瘤发生。在异种移植中，将MRS2578与依托泊苷联合使用，与单独使用每种药物相比，表现出协同抗肿瘤细胞毒性。我们的联合方法引入了一种提高基因毒性疗法治疗肿瘤疗效的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/2f51d5a7fdc8/elife-27301-fig7-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/37cbb0f195c3/elife-27301-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/6c3940915da2/elife-27301-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/e4c04e234a76/elife-27301-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/32b1d6ff24a8/elife-27301-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/893986b461bc/elife-27301-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/c5cc87b4206a/elife-27301-fig2-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/ffe82c8ead9f/elife-27301-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/4153fe1fae21/elife-27301-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/0718a521582d/elife-27301-fig3-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/a76a03e76538/elife-27301-fig3-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/49b8f213101e/elife-27301-fig3-figsupp4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/82b17233cfbf/elife-27301-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/3fab25cc86a5/elife-27301-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/bbf702c34155/elife-27301-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/71161081065a/elife-27301-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/7647445d9332/elife-27301-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/9468cc0ea04e/elife-27301-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/5adf1b6ef6d2/elife-27301-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/4bc127bb8037/elife-27301-fig7-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/7d5f662b8caa/elife-27301-fig7-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/2f51d5a7fdc8/elife-27301-fig7-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/37cbb0f195c3/elife-27301-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/6c3940915da2/elife-27301-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/e4c04e234a76/elife-27301-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/32b1d6ff24a8/elife-27301-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/893986b461bc/elife-27301-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/c5cc87b4206a/elife-27301-fig2-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/ffe82c8ead9f/elife-27301-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/4153fe1fae21/elife-27301-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/0718a521582d/elife-27301-fig3-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/a76a03e76538/elife-27301-fig3-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/49b8f213101e/elife-27301-fig3-figsupp4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/82b17233cfbf/elife-27301-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/3fab25cc86a5/elife-27301-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/bbf702c34155/elife-27301-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/71161081065a/elife-27301-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/7647445d9332/elife-27301-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/9468cc0ea04e/elife-27301-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/5adf1b6ef6d2/elife-27301-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/4bc127bb8037/elife-27301-fig7-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/7d5f662b8caa/elife-27301-fig7-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508e/5562444/2f51d5a7fdc8/elife-27301-fig7-figsupp3.jpg

相似文献

1
Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy.阻断LRP16-PKR-NF-κB信号轴可使结肠癌细胞对DNA损伤性细胞毒性疗法敏感。
Elife. 2017 Aug 18;6:e27301. doi: 10.7554/eLife.27301.
2
An ATM/TRIM37/NEMO Axis Counteracts Genotoxicity by Activating Nuclear-to-Cytoplasmic NF-κB Signaling.ATM/TRIM37/NEMO 轴通过激活核质 NF-κB 信号来对抗遗传毒性。
Cancer Res. 2018 Nov 15;78(22):6399-6412. doi: 10.1158/0008-5472.CAN-18-2063. Epub 2018 Sep 25.
3
LRP16 integrates into NF-κB transcriptional complex and is required for its functional activation.LRP16 整合到 NF-κB 转录复合物中，并需要其功能激活。
PLoS One. 2011 Mar 31;6(3):e18157. doi: 10.1371/journal.pone.0018157.
4
PACT-mediated PKR activation acts as a hyperosmotic stress intensity sensor weakening osmoadaptation and enhancing inflammation.PACT 介导的 PKR 激活作为一种高渗应激强度传感器，削弱了渗透适应，增强了炎症反应。
Elife. 2020 Mar 16;9:e52241. doi: 10.7554/eLife.52241.
5
Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-κB activation.Sam68/KHDRBS1通过调节基因毒性应激诱导的NF-κB激活对结肠癌发生至关重要。
Elife. 2016 Jul 25;5:e15018. doi: 10.7554/eLife.15018.
6
An LRP16-containing preassembly complex contributes to NF-κB activation induced by DNA double-strand breaks.一个含LRP16的预组装复合物有助于由DNA双链断裂诱导的NF-κB激活。
Nucleic Acids Res. 2015 Mar 31;43(6):3167-79. doi: 10.1093/nar/gkv161. Epub 2015 Mar 3.
7
The N-terminus of PKR is responsible for the activation of the NF-kappaB signaling pathway by interacting with the IKK complex.PKR的N端通过与IKK复合物相互作用来激活NF-κB信号通路。
Cell Signal. 2006 Nov;18(11):1865-75. doi: 10.1016/j.cellsig.2006.02.010. Epub 2006 Feb 28.
8
KINK-1, a novel small-molecule inhibitor of IKKbeta, and the susceptibility of melanoma cells to antitumoral treatment.KINK-1，一种新型的IKKβ小分子抑制剂，以及黑色素瘤细胞对抗肿瘤治疗的敏感性。
J Natl Cancer Inst. 2008 Jun 18;100(12):862-75. doi: 10.1093/jnci/djn174. Epub 2008 Jun 10.
9
Concurrent blockade of the NF-kappaB and Akt pathways potently sensitizes cancer cells to chemotherapeutic-induced cytotoxicity.同时阻断 NF-κB 和 Akt 通路可显著增强癌细胞对化疗诱导的细胞毒性的敏感性。
Cancer Lett. 2010 Sep 1;295(1):38-43. doi: 10.1016/j.canlet.2010.02.011. Epub 2010 Mar 5.
10
Inducible chemoresistance to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothe cin (CPT-11) in colorectal cancer cells and a xenograft model is overcome by inhibition of nuclear factor-kappaB activation.通过抑制核因子-κB激活可克服大肠癌细胞及异种移植模型中对7-乙基-10-[4-(1-哌啶基)-1-哌啶基]-羰氧基喜树碱（CPT-11）的诱导性化学抗性。
Cancer Res. 2000 May 1;60(9):2323-30.

引用本文的文献

1
Single-cell and spatial analyses of the GDF family in tumors, with a focus on the prognostic and biological role of GDF15 in hepatocellular carcinoma.肿瘤中GDF家族的单细胞和空间分析，重点关注GDF15在肝细胞癌中的预后和生物学作用。
Cell Biosci. 2025 Jun 27;15(1):92. doi: 10.1186/s13578-025-01431-9.
2
A multidimensional recommendation framework for identifying biological targets to aid the diagnosis and treatment of liver metastasis in patients with colorectal cancer.一种多维推荐框架，用于识别生物靶标，以辅助结直肠癌肝转移患者的诊断和治疗。
Mol Cancer. 2024 Oct 24;23(1):239. doi: 10.1186/s12943-024-02155-z.
3
Discovery of 2-Amide-3-methylester Thiophenes that Target SARS-CoV-2 Mac1 and Repress Coronavirus Replication, Validating Mac1 as an Antiviral Target.

本文引用的文献

1
Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action.诱杀癌细胞：PARP 抑制剂及其作用机制。
Sci Transl Med. 2016 Oct 26;8(362):362ps17. doi: 10.1126/scitranslmed.aaf9246.
2
Activation of the A2A adenosine G-protein-coupled receptor by conformational selection.通过构象选择激活 A2A 腺苷 G 蛋白偶联受体。
Nature. 2016 May 12;533(7602):265-8. doi: 10.1038/nature17668. Epub 2016 May 4.
3
Targeting the DNA Damage Response in Cancer.靶向癌症的 DNA 损伤反应。
发现靶向 SARS-CoV-2 Mac1 的 2-酰胺-3-甲酯噻吩并抑制冠状病毒复制，验证 Mac1 为抗病毒靶点。
J Med Chem. 2024 Apr 25;67(8):6519-6536. doi: 10.1021/acs.jmedchem.3c02451. Epub 2024 Apr 9.
4
Discovery of 2-amide-3-methylester thiophenes that target SARS-CoV-2 Mac1 and repress coronavirus replication, validating Mac1 as an anti-viral target.发现靶向新冠病毒Mac1并抑制冠状病毒复制的2-酰胺基-3-甲酯噻吩，验证了Mac1作为抗病毒靶点的作用。
bioRxiv. 2023 Dec 27:2023.08.28.555062. doi: 10.1101/2023.08.28.555062.
5
Mechanism of herpesvirus protein kinase UL13 in immune escape and viral replication.疱疹病毒蛋白激酶 UL13 在免疫逃避和病毒复制中的作用机制。
Front Immunol. 2022 Nov 30;13:1088690. doi: 10.3389/fimmu.2022.1088690. eCollection 2022.
6
Direct and indirect effects of IFN-α2b in malignancy treatment: not only an archer but also an arrow.IFN-α2b在恶性肿瘤治疗中的直接和间接作用：既是射手也是箭。
Biomark Res. 2022 Sep 14;10(1):69. doi: 10.1186/s40364-022-00415-y.
7
Macrodomain Binding Compound MRS 2578 Inhibits Alphavirus Replication.大环结构域结合化合物 MRS 2578 抑制甲病毒复制。
Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0139821. doi: 10.1128/AAC.01398-21. Epub 2021 Oct 4.
8
A tale of two proteins: PACT and PKR and their roles in inflammation.两种蛋白的故事：PACT 和 PKR 及其在炎症中的作用。
FEBS J. 2021 Nov;288(22):6365-6391. doi: 10.1111/febs.15691. Epub 2021 Jan 15.
9
Histone Deacetylase Inhibitors to Overcome Resistance to Targeted and Immuno Therapy in Metastatic Melanoma.组蛋白去乙酰化酶抑制剂用于克服转移性黑色素瘤对靶向治疗和免疫治疗的耐药性
Front Cell Dev Biol. 2020 Jun 17;8:486. doi: 10.3389/fcell.2020.00486. eCollection 2020.
10
The Controversial Roles of ADP-Ribosyl Hydrolases MACROD1, MACROD2 and TARG1 in Carcinogenesis.ADP核糖水解酶MACROD1、MACROD2和TARG1在肿瘤发生中的争议性作用
Cancers (Basel). 2020 Mar 5;12(3):604. doi: 10.3390/cancers12030604.
Mol Cell. 2015 Nov 19;60(4):547-60. doi: 10.1016/j.molcel.2015.10.040.
4
DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.转移性前列腺癌中的DNA修复缺陷与奥拉帕利
N Engl J Med. 2015 Oct 29;373(18):1697-708. doi: 10.1056/NEJMoa1506859.
5
An LRP16-containing preassembly complex contributes to NF-κB activation induced by DNA double-strand breaks.一个含LRP16的预组装复合物有助于由DNA双链断裂诱导的NF-κB激活。
Nucleic Acids Res. 2015 Mar 31;43(6):3167-79. doi: 10.1093/nar/gkv161. Epub 2015 Mar 3.
6
Lack of effect of a P2Y6 receptor antagonist on neuropathic pain behavior in mice.P2Y6受体拮抗剂对小鼠神经性疼痛行为无影响。
Pharmacol Biochem Behav. 2014 Sep;124:389-95. doi: 10.1016/j.pbb.2014.07.009. Epub 2014 Jul 18.
7
Whole-exome sequencing of endometriosis identifies frequent alterations in genes involved in cell adhesion and chromatin-remodeling complexes.子宫内膜异位症的全外显子组测序确定了参与细胞黏附和染色质重塑复合体的基因中的常见改变。
Hum Mol Genet. 2014 Nov 15;23(22):6008-21. doi: 10.1093/hmg/ddu330. Epub 2014 Jun 26.
8
The impact of PKR activation: from neurodegeneration to cancer.PKR 激活的影响：从神经退行性变到癌症。
FASEB J. 2014 May;28(5):1965-74. doi: 10.1096/fj.13-248294. Epub 2014 Feb 12.
9
Mechanisms of resistance to therapies targeting BRCA-mutant cancers.针对 BRCA 突变型癌症的治疗的耐药机制。
Nat Med. 2013 Nov;19(11):1381-8. doi: 10.1038/nm.3369. Epub 2013 Oct 7.
10
Cancer drug resistance: an evolving paradigm.癌症耐药性：一个不断发展的范式。
Nat Rev Cancer. 2013 Oct;13(10):714-26. doi: 10.1038/nrc3599.