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KU0060648靶向过度激活的DNA依赖性蛋白激酶催化亚基（DNA-PKcs）可抑制胶质瘤进展，并通过抑制AKT信号增强替莫唑胺治疗效果。

Targeting hyperactivated DNA-PKcs by KU0060648 inhibits glioma progression and enhances temozolomide therapy via suppression of AKT signaling.

作者信息

Lan Tian, Zhao Zitong, Qu Yanming, Zhang Mingshan, Wang Haoran, Zhang Zhihua, Zhou Wei, Fan Xinyi, Yu Chunjiang, Zhan Qimin, Song Yongmei

机构信息

State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China.

出版信息

Oncotarget. 2016 Aug 23;7(34):55555-55571. doi: 10.18632/oncotarget.10864.

DOI:10.18632/oncotarget.10864
PMID:27487130
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5342436/
Abstract

The overall survival remains undesirable in clinical glioma treatment. Inhibition of DNA-PKcs activity by its inhibitors suppresses tumor growth and enhances chemosensitivity of several tumors to chemotherapy. However, whether DNA-PKcs could be a potential target in glioma therapy remains unknown. In this study, we reported that the hyperactivated DNA-PKcs was profoundly correlated with glioma malignancy and observe a significant association between DNA-PKcs activation and survival of the glioma patients. Our data also found that inhibition of DNA-PKcs by its inhibitor KU0060648 sensitized glioma cells to TMZ in vitro. Specifically, we demonstrated that KU0060648 interrupted the formation of DNA-PKcs/AKT complex, leading to suppression of AKT signaling and resultantly enhanced TMZ efficacy. Combination of KU0060648 and TMZ substantially inhibited downstream effectors of AKT. The in vivo results were similar to those obtained in vitro. In conclusion, this study indicated that inhibition of DNA-PKcs activity could suppress glioma malignancies and increase TMZ efficacy, which was mainly through regulation of the of AKT signaling. Therefore, DNA-PKcs/AKT axis may be a promising target for improving current glioma therapy.

摘要

在临床胶质瘤治疗中，总体生存率仍不尽人意。其抑制剂对DNA-PKcs活性的抑制作用可抑制肿瘤生长，并增强多种肿瘤对化疗的敏感性。然而，DNA-PKcs是否可能成为胶质瘤治疗的潜在靶点仍不清楚。在本研究中，我们报告了过度激活的DNA-PKcs与胶质瘤恶性程度密切相关，并观察到DNA-PKcs激活与胶质瘤患者生存率之间存在显著关联。我们的数据还发现，其抑制剂KU0060648对DNA-PKcs的抑制作用在体外使胶质瘤细胞对替莫唑胺（TMZ）敏感。具体而言，我们证明KU0060648中断了DNA-PKcs/AKT复合物的形成，导致AKT信号传导受到抑制，从而提高了TMZ的疗效。KU0060648与TMZ联合使用可显著抑制AKT的下游效应分子。体内结果与体外结果相似。总之，本研究表明，抑制DNA-PKcs活性可抑制胶质瘤恶性程度并提高TMZ疗效，这主要是通过调节AKT信号传导实现的。因此，DNA-PKcs/AKT轴可能是改善当前胶质瘤治疗的一个有前景的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cd9/5342436/d6a6e0b61646/oncotarget-07-55555-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cd9/5342436/dc40af616998/oncotarget-07-55555-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cd9/5342436/428e584156f7/oncotarget-07-55555-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cd9/5342436/560a3d044e67/oncotarget-07-55555-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cd9/5342436/d6a6e0b61646/oncotarget-07-55555-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cd9/5342436/dc40af616998/oncotarget-07-55555-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cd9/5342436/746bcaa54813/oncotarget-07-55555-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cd9/5342436/961aa6160282/oncotarget-07-55555-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cd9/5342436/820e1c7bf7b9/oncotarget-07-55555-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cd9/5342436/428e584156f7/oncotarget-07-55555-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cd9/5342436/560a3d044e67/oncotarget-07-55555-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cd9/5342436/d6a6e0b61646/oncotarget-07-55555-g007.jpg

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1
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2
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Cell Cycle. 2015;14(12):1961-72. doi: 10.1080/15384101.2015.1026522.
3
Effects of conventional neoadjuvant chemotherapy for breast cancer on tumor angiogenesis.
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Neurooncol Adv. 2022 Sep 25;4(1):vdac156. doi: 10.1093/noajnl/vdac156. eCollection 2022 Jan-Dec.
4
EGFR suppresses p53 function by promoting p53 binding to DNA-PKcs: a noncanonical regulatory axis between EGFR and wild-type p53 in glioblastoma.表皮生长因子受体（EGFR）通过促进 p53 与 DNA 依赖性蛋白激酶催化亚基（DNA-PKcs）结合来抑制 p53 功能：胶质母细胞瘤中 EGFR 和野生型 p53 之间的非典型调控轴。
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5
Development and Evolution of DNA-Dependent Protein Kinase Inhibitors toward Cancer Therapy.DNA 依赖性蛋白激酶抑制剂的发展与演进及其在癌症治疗中的应用。
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6
Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma.关于使用DNA修复抑制剂作为胶质母细胞瘤成像和放射性核素治疗工具的观点。
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8
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10
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4
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5
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7
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J Cell Physiol. 2015 May;230(5):1094-103. doi: 10.1002/jcp.24841.