• 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

端锚聚合酶抑制剂G007-LK可抑制小肠LGR5干细胞增殖，且不改变组织形态。

The tankyrase inhibitor G007-LK inhibits small intestine LGR5 stem cell proliferation without altering tissue morphology.

作者信息

Norum Jens Henrik, Skarpen Ellen, Brech Andreas, Kuiper Raoul, Waaler Jo, Krauss Stefan, Sørlie Therese

机构信息

Department of Cancer Genetics and SFI CAST, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, 0310, Oslo, Norway.

Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, 0310, Oslo, Norway.

出版信息

Biol Res. 2018 Jan 9;51(1):3. doi: 10.1186/s40659-017-0151-6.

DOI:10.1186/s40659-017-0151-6
PMID:29316982
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5759193/
Abstract

BACKGROUND

The WNT pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes tankyrase1 and 2. LGR5 is a known WNT pathway target gene and marker of intestinal stem cells. The LGR5 stem cells are located in the crypt base and capable of regenerating all intestinal epithelial cell lineages.

RESULTS

We treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice with the tankyrase inhibitor G007-LK for up to 3 weeks to assess the effect on duodenal stem cell homeostasis and on the integrity of intestinal epithelium. At the administered doses, G007-LK treatment inhibited WNT signalling in LGR5 stem cells and reduced the number and distribution of cells traced from duodenal LGR5 stem cells. However, the gross morphology of the duodenum remained unaltered and G007-LK-treated mice showed no signs of weight loss or any other visible morphological changes. The inhibitory effect on LGR5 stem cell proliferation was reversible.

CONCLUSION

We show that the tankyrase inhibitor G007-LK is well tolerated by the mice, although proliferation of the LGR5 intestinal stem cells was inhibited. Our observations suggest the presence of a tankyrase inhibitor-resistant cell population in the duodenum, able to rescue tissue integrity in the presence of G007-LK-mediated inhibition of the WNT signalling dependent LGR5 intestinal epithelial stem cells.

摘要

背景

WNT信号通路调控肠道干细胞，且在肠道腺瘤中常被破坏。该通路包含几个潜在的可干扰生物靶点，包括聚ADP核糖基转移酶端粒酶1和2。LGR5是已知的WNT信号通路靶基因和肠道干细胞标志物。LGR5干细胞位于隐窝底部，能够再生所有肠道上皮细胞谱系。

结果

我们用端粒酶抑制剂G007-LK处理Lgr5-EGFP-Ires-CreERT2;R26R-Confetti小鼠长达3周，以评估其对十二指肠干细胞稳态和肠道上皮完整性的影响。在给药剂量下，G007-LK处理抑制了LGR5干细胞中的WNT信号传导，并减少了源自十二指肠LGR5干细胞的细胞数量和分布。然而，十二指肠的大体形态保持不变，G007-LK处理的小鼠没有体重减轻或任何其他可见形态变化的迹象。对LGR5干细胞增殖的抑制作用是可逆的。

结论

我们表明，尽管LGR5肠道干细胞的增殖受到抑制，但端粒酶抑制剂G007-LK在小鼠中耐受性良好。我们的观察结果表明，十二指肠中存在对端粒酶抑制剂耐药的细胞群体，能够在G007-LK介导的对依赖WNT信号传导的LGR5肠道上皮干细胞的抑制作用下挽救组织完整性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5f/5759193/06438cb7497a/40659_2017_151_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5f/5759193/b40f09b58bd1/40659_2017_151_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5f/5759193/61aa0ebde4ca/40659_2017_151_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5f/5759193/32e7fd8b7d93/40659_2017_151_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5f/5759193/16e19882f391/40659_2017_151_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5f/5759193/06438cb7497a/40659_2017_151_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5f/5759193/b40f09b58bd1/40659_2017_151_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5f/5759193/61aa0ebde4ca/40659_2017_151_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5f/5759193/32e7fd8b7d93/40659_2017_151_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5f/5759193/16e19882f391/40659_2017_151_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5f/5759193/06438cb7497a/40659_2017_151_Fig5_HTML.jpg

相似文献

1
The tankyrase inhibitor G007-LK inhibits small intestine LGR5 stem cell proliferation without altering tissue morphology.端锚聚合酶抑制剂G007-LK可抑制小肠LGR5干细胞增殖，且不改变组织形态。
Biol Res. 2018 Jan 9;51(1):3. doi: 10.1186/s40659-017-0151-6.
2
A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth.一种新型 Tankyrase 小分子抑制剂抑制 APC 突变驱动的结直肠肿瘤生长。
Cancer Res. 2013 May 15;73(10):3132-44. doi: 10.1158/0008-5472.CAN-12-4562. Epub 2013 Mar 28.
3
Structure, Dynamics, and Functionality of Tankyrase Inhibitor-Induced Degradasomes. Tankyrase 抑制剂诱导的降解酶体的结构、动态和功能。
Mol Cancer Res. 2015 Nov;13(11):1487-501. doi: 10.1158/1541-7786.MCR-15-0125. Epub 2015 Jun 29.
4
Pharmacological inhibition of tankyrase induces bone loss in mice by increasing osteoclastogenesis.抑制 Tankyrase 可通过增加破骨细胞生成诱导小鼠骨丢失。
Bone. 2018 Jan;106:156-166. doi: 10.1016/j.bone.2017.10.017. Epub 2017 Oct 18.
5
Structural basis and SAR for G007-LK, a lead stage 1,2,4-triazole based specific tankyrase 1/2 inhibitor.基于结构的 G007-LK 的作用机制和 SAR 研究，一种先导化合物，1,2,4-三唑类靶向 tankyrase 1/2 的抑制剂。
J Med Chem. 2013 Apr 11;56(7):3012-23. doi: 10.1021/jm4000566. Epub 2013 Mar 29.
6
Lgr5-expressing stem cells are not the cells of origin of pyloric neuroendocrine carcinomas in mice.表达Lgr5的干细胞不是小鼠幽门神经内分泌癌的起源细胞。
J Pathol. 2016 Jan;238(1):42-51. doi: 10.1002/path.4629. Epub 2015 Oct 1.
7
Tankyrases maintain homeostasis of intestinal epithelium by preventing cell death.端锚聚合酶通过防止细胞死亡来维持肠道上皮细胞的内稳态。
PLoS Genet. 2018 Sep 27;14(9):e1007697. doi: 10.1371/journal.pgen.1007697. eCollection 2018 Sep.
8
Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models.端锚聚合酶抑制增强了 PD-1 免疫检查点阻断在同基因小鼠模型中的黑色素瘤疗效。
Commun Biol. 2020 Apr 24;3(1):196. doi: 10.1038/s42003-020-0916-2.
9
RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model.RK-287107 是一种强效且特异性的 tankyrase 抑制剂，可在临床前模型中阻断结直肠癌细胞生长。
Cancer Sci. 2018 Dec;109(12):4003-4014. doi: 10.1111/cas.13805. Epub 2018 Oct 20.
10
Arsenic exposure in drinking water reduces Lgr5 and secretory cell marker gene expression in mouse intestines.饮用水中的砷暴露会降低小鼠肠道中的 Lgr5 和分泌细胞标记基因的表达。
Toxicol Appl Pharmacol. 2021 Jul 1;422:115561. doi: 10.1016/j.taap.2021.115561. Epub 2021 May 3.

引用本文的文献

1
Wnt/β-Catenin Signaling Regulates Hepatitis B Virus cccDNA Levels.Wnt/β-连环蛋白信号通路调控乙型肝炎病毒共价闭合环状DNA水平。
Int J Mol Sci. 2025 Jul 19;26(14):6942. doi: 10.3390/ijms26146942.
2
Rare histologic transformation of a CTNNB1 (β-catenin) mutated prostate cancer with aggressive clinical course.CTNNB1（β-连环蛋白）突变型前列腺癌的罕见组织学转化伴侵袭性临床病程。
Diagn Pathol. 2024 Jun 21;19(1):83. doi: 10.1186/s13000-024-01511-3.
3
A Mouse Model for the Rapid and Binomial Assessment of Putative WNT/β-Catenin Signalling Inhibitors.

本文引用的文献

1
Wnt/β-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor.Wnt/β-catenin 信号通路促进胃肠间质瘤的肿瘤恶性进展并可作为治疗靶点。
Mol Cancer Ther. 2017 Sep;16(9):1954-1966. doi: 10.1158/1535-7163.MCT-17-0139. Epub 2017 Jun 13.
2
Tankyrase Inhibition Causes Reversible Intestinal Toxicity in Mice with a Therapeutic Index < 1.端锚聚合酶抑制对治疗指数<1的小鼠会造成可逆性肠道毒性。
Toxicol Pathol. 2016 Feb;44(2):267-78. doi: 10.1177/0192623315621192. Epub 2015 Dec 20.
3
The PARsylation activity of tankyrase in adipose tissue modulates systemic glucose metabolism in mice.
一种用于快速和二项式评估假定的WNT/β-连环蛋白信号通路抑制剂的小鼠模型。
Biomedicines. 2023 Oct 7;11(10):2719. doi: 10.3390/biomedicines11102719.
4
Wnt Signaling Inhibitors and Their Promising Role in Tumor Treatment.Wnt 信号抑制剂及其在肿瘤治疗中的应用前景。
Int J Mol Sci. 2023 Apr 4;24(7):6733. doi: 10.3390/ijms24076733.
5
The Tankyrase Inhibitor OM-153 Demonstrates Antitumor Efficacy and a Therapeutic Window in Mouse Models.Tankyrase 抑制剂 OM-153 在小鼠模型中表现出抗肿瘤疗效和治疗窗口。
Cancer Res Commun. 2022 Apr 20;2(4):233-245. doi: 10.1158/2767-9764.CRC-22-0027. eCollection 2022 Apr.
6
Blocking the Wnt/β‑catenin signaling pathway to treat colorectal cancer: Strategies to improve current therapies (Review).阻断 Wnt/β-连环蛋白信号通路治疗结直肠癌：改善现有疗法的策略（综述）。
Int J Oncol. 2023 Feb;62(2). doi: 10.3892/ijo.2022.5472. Epub 2022 Dec 29.
7
Tankyrases as modulators of pro-tumoral functions: molecular insights and therapeutic opportunities.端锚聚合酶作为促进肿瘤功能的调节剂：分子见解与治疗机会。
J Exp Clin Cancer Res. 2021 Apr 28;40(1):144. doi: 10.1186/s13046-021-01950-6.
8
The dual pocket binding novel tankyrase inhibitor K-476 enhances the efficacy of immune checkpoint inhibitor by attracting CD8 T cells to tumors.双口袋结合型新型端锚聚合酶抑制剂K-476通过吸引CD8 T细胞至肿瘤部位来增强免疫检查点抑制剂的疗效。
Am J Cancer Res. 2021 Jan 1;11(1):264-276. eCollection 2021.
9
Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor.基于 1,2,4-三唑的 Tankyrase 抑制剂的临床前先导优化。
J Med Chem. 2020 Jul 9;63(13):6834-6846. doi: 10.1021/acs.jmedchem.0c00208. Epub 2020 Jun 23.
10
Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models.端锚聚合酶抑制增强了 PD-1 免疫检查点阻断在同基因小鼠模型中的黑色素瘤疗效。
Commun Biol. 2020 Apr 24;3(1):196. doi: 10.1038/s42003-020-0916-2.
端锚聚合酶在脂肪组织中的聚腺苷酸化核糖基化活性调节小鼠的全身葡萄糖代谢。
Diabetologia. 2016 Mar;59(3):582-91. doi: 10.1007/s00125-015-3815-1. Epub 2015 Dec 2.
4
Structure, Dynamics, and Functionality of Tankyrase Inhibitor-Induced Degradasomes. Tankyrase 抑制剂诱导的降解酶体的结构、动态和功能。
Mol Cancer Res. 2015 Nov;13(11):1487-501. doi: 10.1158/1541-7786.MCR-15-0125. Epub 2015 Jun 29.
5
Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43;Znrf3-mutant neoplasia.豪猪抑制剂可抑制旁分泌Wnt驱动的Rnf43;Znrf3突变肿瘤的生长。
Proc Natl Acad Sci U S A. 2015 Jun 16;112(24):7548-50. doi: 10.1073/pnas.1508113112. Epub 2015 May 28.
6
A conditional transgenic mouse line for targeted expression of the stem cell marker LGR5.一种用于靶向表达干细胞标志物LGR5的条件性转基因小鼠品系。
Dev Biol. 2015 Aug 15;404(2):35-48. doi: 10.1016/j.ydbio.2015.05.002. Epub 2015 May 21.
7
Can we safely target the WNT pathway?我们能否安全地靶向WNT信号通路？
Nat Rev Drug Discov. 2014 Jul;13(7):513-32. doi: 10.1038/nrd4233.
8
Tankyrases: structure, function and therapeutic implications in cancer.端粒酶：结构、功能及在癌症治疗中的意义
Curr Pharm Des. 2014;20(41):6472-88. doi: 10.2174/1381612820666140630101525.
9
Tankyrases as drug targets.端锚聚合酶作为药物靶点。
FEBS J. 2013 Aug;280(15):3576-93. doi: 10.1111/febs.12320. Epub 2013 Jun 18.
10
Evidence for tankyrases as antineoplastic targets in lung cancer.在肺癌中作为抗肿瘤靶标的 Tankyrases 的证据。
BMC Cancer. 2013 Apr 28;13:211. doi: 10.1186/1471-2407-13-211.