• 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

Notch-1 通过激活 IGF-1R 通路促进低氧环境下肺腺癌细胞的存活。

Notch-1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathway.

机构信息

Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153, USA.

出版信息

Oncogene. 2010 Apr 29;29(17):2488-98. doi: 10.1038/onc.2010.7. Epub 2010 Feb 15.

DOI:10.1038/onc.2010.7
PMID:20154720
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2861728/
Abstract

Hypoxic microenvironment supports cancer stem cell survival, causes poor response to anticancer therapy and tumor recurrence. Inhibition of Notch-1 signaling in adenocarcinoma of the lung (ACL) cells causes apoptosis specifically under hypoxia. Here, we found that Akt-1 activation is a key mediator of Notch-1 pro-survival effects under hypoxia. Notch-1 activates Akt-1 through repression of phosphatase and tensin (PTEN) homolog expression and induction of the insulin-like growth factor 1 receptor (IGF-1R). The latter seems to be the major determinant of Akt-1 stimulation, as Notch-1 signaling affects Akt-1 activation in PTEN(-/-) ACL cells. Both downregulation of insulin receptor substrate 1 (IRS-1) and dominant-negative IGF-1R sensitized ACL cells to gamma-secretase inhibitor (GSI)-induced apoptosis. Conversely, overexpression of IGF-1R protected ACL cells from GSI toxicity. Inhibition of Notch-1 caused reduced IGF-1R expression, whereas forced Notch-1 expression yielded opposite effects. Chromatin immunoprecipitation experiments suggested Notch-1 direct regulation of the IGF-1R promoter. Experiments in which human ACL cells were injected in mice confirmed elevated and specific co-expression of Notch-1(IC), IGF-1R and pAkt-1 in hypoxic tumor areas. Our data provide a mechanistic explanation for Notch-1-mediated pro-survival function in hypoxic ACL tumor microenvironment. The results identify additional targets that may synergize with Notch-1 inhibition for ACL treatment.

摘要

缺氧微环境支持癌症干细胞的存活，导致对癌症治疗和肿瘤复发的反应不佳。在肺腺癌 (ACL) 细胞中抑制 Notch-1 信号通路会导致缺氧下的细胞凋亡。在这里，我们发现 Akt-1 的激活是 Notch-1 在缺氧下促进存活的关键介质。Notch-1 通过抑制磷酸酶和张力蛋白 (PTEN) 同源物的表达和诱导胰岛素样生长因子 1 受体 (IGF-1R) 的表达来激活 Akt-1。后者似乎是 Akt-1 刺激的主要决定因素，因为 Notch-1 信号通路会影响 PTEN(-/-) ACL 细胞中 Akt-1 的激活。胰岛素受体底物 1 (IRS-1) 的下调和显性失活 IGF-1R 均使 ACL 细胞对 γ-分泌酶抑制剂 (GSI) 诱导的细胞凋亡敏感。相反，IGF-1R 的过表达可保护 ACL 细胞免受 GSI 的毒性。Notch-1 的抑制导致 IGF-1R 表达减少，而强制 Notch-1 表达则产生相反的效果。染色质免疫沉淀实验表明 Notch-1 可直接调节 IGF-1R 启动子。在将人 ACL 细胞注射到小鼠中的实验中，证实了 Notch-1(IC)、IGF-1R 和 pAkt-1 在缺氧肿瘤区域的高表达和特异性共表达。我们的数据为 Notch-1 在缺氧 ACL 肿瘤微环境中促进存活的功能提供了机制解释。这些结果确定了其他可能与 Notch-1 抑制协同作用以治疗 ACL 的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43a/2861728/9904ad9cd0b4/nihms169011f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43a/2861728/a33f81f93fd9/nihms169011f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43a/2861728/d36fde6050fb/nihms169011f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43a/2861728/0223fa33a9b9/nihms169011f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43a/2861728/51ca5cdf5a28/nihms169011f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43a/2861728/1c6e01b0d7d5/nihms169011f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43a/2861728/43c53f238095/nihms169011f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43a/2861728/9904ad9cd0b4/nihms169011f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43a/2861728/a33f81f93fd9/nihms169011f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43a/2861728/d36fde6050fb/nihms169011f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43a/2861728/0223fa33a9b9/nihms169011f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43a/2861728/51ca5cdf5a28/nihms169011f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43a/2861728/1c6e01b0d7d5/nihms169011f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43a/2861728/43c53f238095/nihms169011f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43a/2861728/9904ad9cd0b4/nihms169011f7.jpg

相似文献

1
Notch-1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathway. Notch-1 通过激活 IGF-1R 通路促进低氧环境下肺腺癌细胞的存活。
Oncogene. 2010 Apr 29;29(17):2488-98. doi: 10.1038/onc.2010.7. Epub 2010 Feb 15.
2
Notch1 receptor regulates AKT protein activation loop (Thr308) dephosphorylation through modulation of the PP2A phosphatase in phosphatase and tensin homolog (PTEN)-null T-cell acute lymphoblastic leukemia cells.Notch1 受体通过调节磷酸酶和张力蛋白同源物（PTEN）缺失型 T 细胞急性淋巴细胞白血病细胞中的蛋白磷酸酶 2A（PP2A）来调节 AKT 蛋白激活环（Thr308）去磷酸化。
J Biol Chem. 2013 Aug 2;288(31):22836-48. doi: 10.1074/jbc.M113.451625. Epub 2013 Jun 20.
3
Decreased IGF type 1 receptor signaling in mammary epithelium during pregnancy leads to reduced proliferation, alveolar differentiation, and expression of insulin receptor substrate (IRS)-1 and IRS-2.妊娠期间乳腺上皮中 IGF 类型 1 受体信号的减少导致增殖减少、肺泡分化减少以及胰岛素受体底物 (IRS)-1 和 IRS-2 的表达减少。
Endocrinology. 2011 Aug;152(8):3233-45. doi: 10.1210/en.2010-1296. Epub 2011 May 31.
4
Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung.氧浓度决定了NOTCH-1信号通路在肺腺癌中的生物学效应。
Cancer Res. 2007 Sep 1;67(17):7954-9. doi: 10.1158/0008-5472.CAN-07-1229.
5
Opposite effects of Notch-1 and Notch-2 on mesothelioma cell survival under hypoxia are exerted through the Akt pathway.Notch-1和Notch-2在缺氧条件下对间皮瘤细胞存活产生的相反作用是通过Akt信号通路发挥的。
Cancer Res. 2008 Dec 1;68(23):9678-85. doi: 10.1158/0008-5472.CAN-08-0969.
6
Selective inhibition of SCLC growth by the A12 anti-IGF-1R monoclonal antibody correlates with inhibition of Akt.A12抗IGF-1R单克隆抗体对小细胞肺癌生长的选择性抑制与Akt的抑制相关。
Lung Cancer. 2008 May;60(2):166-74. doi: 10.1016/j.lungcan.2007.09.023. Epub 2007 Nov 14.
7
The expression and significance of insulin-like growth factor-1 receptor and its pathway on breast cancer stem/progenitors.胰岛素样生长因子-1受体及其信号通路在乳腺癌干细胞/祖细胞中的表达及意义
Breast Cancer Res. 2013 May 12;15(3):R39. doi: 10.1186/bcr3423.
8
β-Catenin/POU5F1/SOX2 transcription factor complex mediates IGF-I receptor signaling and predicts poor prognosis in lung adenocarcinoma.β-连环蛋白/POU5F1/SOX2 转录因子复合物介导 IGF-I 受体信号转导，并预测肺腺癌的不良预后。
Cancer Res. 2013 May 15;73(10):3181-9. doi: 10.1158/0008-5472.CAN-12-4403. Epub 2013 Mar 28.
9
Estrogen and insulin-like growth factor 1 synergistically promote the development of lung adenocarcinoma in mice.雌激素和胰岛素样生长因子 1 协同促进小鼠肺腺癌的发展。
Int J Cancer. 2013 Nov 15;133(10):2473-82. doi: 10.1002/ijc.28262. Epub 2013 Jun 12.
10
FAK and IGF-IR interact to provide survival signals in human pancreatic adenocarcinoma cells.粘着斑激酶（FAK）与胰岛素样生长因子1受体（IGF-IR）相互作用，为人胰腺腺癌细胞提供存活信号。
Carcinogenesis. 2008 Jun;29(6):1096-107. doi: 10.1093/carcin/bgn026. Epub 2008 Feb 7.

引用本文的文献

1
Chondrosarcoma: Multi-Targeting Therapeutic Effects of Doxorubicin, BEZ235, and the Small Molecule Aspartyl-Asparaginyl-β-hydroxylase Inhibitor SMI1182.软骨肉瘤：阿霉素、BEZ235及小分子天冬氨酰-天冬氨酰胺-β-羟化酶抑制剂SMI1182的多靶点治疗效果
Cancers (Basel). 2025 May 15;17(10):1671. doi: 10.3390/cancers17101671.
2
Emerging role of MYB transcription factors in cancer drug resistance.MYB转录因子在癌症耐药性中的新作用。
Cancer Drug Resist. 2024 Apr 30;7:15. doi: 10.20517/cdr.2023.158. eCollection 2024.
3
The Molecular and Cellular Strategies of Glioblastoma and Non-Small-Cell Lung Cancer Cells Conferring Radioresistance.

本文引用的文献

1
The PI3-K/AKT-pathway and radiation resistance mechanisms in non-small cell lung cancer.非小细胞肺癌中的PI3-K/AKT信号通路与辐射抗性机制
J Thorac Oncol. 2009 Jun;4(6):761-7. doi: 10.1097/JTO.0b013e3181a1084f.
2
HER-2, notch, and breast cancer stem cells: targeting an axis of evil.人表皮生长因子受体2、Notch与乳腺癌干细胞：靶向邪恶轴心
Clin Cancer Res. 2009 Mar 15;15(6):1845-7. doi: 10.1158/1078-0432.CCR-08-3087. Epub 2009 Mar 10.
3
Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis.
胶质母细胞瘤和非小细胞肺癌细胞的分子和细胞策略赋予其放射抵抗性。
Int J Mol Sci. 2022 Nov 5;23(21):13577. doi: 10.3390/ijms232113577.
4
Targeting Growth Factor and Cytokine Pathways to Treat Idiopathic Pulmonary Fibrosis.靶向生长因子和细胞因子通路治疗特发性肺纤维化。
Front Pharmacol. 2022 Jun 3;13:918771. doi: 10.3389/fphar.2022.918771. eCollection 2022.
5
LncRNAs LCETRL3 and LCETRL4 at chromosome 4q12 diminish EGFR-TKIs efficiency in NSCLC through stabilizing TDP43 and EIF2S1.位于 4q12 染色体上的长链非编码 RNA LCETRL3 和 LCETRL4 通过稳定 TDP43 和 EIF2S1 降低 NSCLC 中 EGFR-TKIs 的疗效。
Signal Transduct Target Ther. 2022 Jan 31;7(1):30. doi: 10.1038/s41392-021-00847-2.
6
Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives.靶向Notch以最大化化疗益处：理论依据、先进策略及未来展望。
Cancers (Basel). 2021 Oct 12;13(20):5106. doi: 10.3390/cancers13205106.
7
PKM2 Regulates HSP90-Mediated Stability of the IGF-1R Precursor Protein and Promotes Cancer Cell Survival during Hypoxia.丙酮酸激酶M2调节热休克蛋白90介导的胰岛素样生长因子-1受体前体蛋白稳定性并促进缺氧时癌细胞存活。
Cancers (Basel). 2021 Jul 30;13(15):3850. doi: 10.3390/cancers13153850.
8
A novel mechanism driving poor-prognostic gastric cancer: overexpression of the transcription factor Krüppel-like factor 16 promotes growth and metastasis of gastric cancer through regulating the Notch pathway.一种驱动预后不良型胃癌的新机制：转录因子Krüppel样因子16的过表达通过调控Notch通路促进胃癌的生长和转移。
Am J Cancer Res. 2021 Jun 15;11(6):2717-2735. eCollection 2021.
9
Niche Modulation of IGF-1R Signaling: Its Role in Stem Cell Pluripotency, Cancer Reprogramming, and Therapeutic Applications.胰岛素样生长因子-1受体（IGF-1R）信号通路的微环境调控：其在干细胞多能性、癌症重编程及治疗应用中的作用
Front Cell Dev Biol. 2021 Jan 12;8:625943. doi: 10.3389/fcell.2020.625943. eCollection 2020.
10
Targeting Notch in oncology: the path forward.靶向 Notch 治疗肿瘤：前进之路。
Nat Rev Drug Discov. 2021 Feb;20(2):125-144. doi: 10.1038/s41573-020-00091-3. Epub 2020 Dec 8.
用强效肿瘤血管生成抑制剂进行短期治疗后转移加速。
Cancer Cell. 2009 Mar 3;15(3):232-9. doi: 10.1016/j.ccr.2009.01.021.
4
Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis.抗血管生成疗法会引发肿瘤的恶性进展，导致局部侵袭增加和远处转移。
Cancer Cell. 2009 Mar 3;15(3):220-31. doi: 10.1016/j.ccr.2009.01.027.
5
Cancer stem cells and tumor response to therapy: current problems and future prospects.癌症干细胞与肿瘤的治疗反应：当前问题与未来前景
Semin Radiat Oncol. 2009 Apr;19(2):96-105. doi: 10.1016/j.semradonc.2008.11.004.
6
Opposite effects of Notch-1 and Notch-2 on mesothelioma cell survival under hypoxia are exerted through the Akt pathway.Notch-1和Notch-2在缺氧条件下对间皮瘤细胞存活产生的相反作用是通过Akt信号通路发挥的。
Cancer Res. 2008 Dec 1;68(23):9678-85. doi: 10.1158/0008-5472.CAN-08-0969.
7
Insulin and insulin-like growth factor signalling in neoplasia.肿瘤形成中的胰岛素及胰岛素样生长因子信号传导
Nat Rev Cancer. 2008 Dec;8(12):915-28. doi: 10.1038/nrc2536.
8
The role of insulin receptor signaling in zebrafish embryogenesis.胰岛素受体信号在斑马鱼胚胎发育中的作用。
Endocrinology. 2008 Dec;149(12):5996-6005. doi: 10.1210/en.2008-0329. Epub 2008 Aug 7.
9
Notch signalling is required for both dauer maintenance and recovery in C. elegans.Notch信号通路对于秀丽隐杆线虫的滞育维持和恢复都是必需的。
Development. 2008 Aug;135(15):2583-92. doi: 10.1242/dev.012435. Epub 2008 Jul 3.
10
The role of insulin receptors and IGF-I receptors in cancer and other diseases.胰岛素受体和胰岛素样生长因子-I受体在癌症及其他疾病中的作用。
Arch Physiol Biochem. 2008 Feb;114(1):23-37. doi: 10.1080/13813450801969715.