Oncotarget

Research Papers:

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

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

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Oncotarget. 2016; 7:55555-55571. https://doi.org/10.18632/oncotarget.10864

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Abstract

Tian Lan1,2,*, Zitong Zhao1,*, Yanming Qu2, Mingshan Zhang2, Haoran Wang2, Zhihua Zhang1,2, Wei Zhou1, Xinyi Fan1, Chunjiang Yu2, Qimin Zhan1, Yongmei Song1

1State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

2Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China

*These authors have contributed equally to this work

Correspondence to:

Yongmei Song, email: symlh2006@163.com

Qimin Zhan, email: zhanqimin@pumc.edu.cn

Chunjiang Yu, email: cjyu1955@sina.com

Keywords: p-DNA-PKcs, glioma, KU0060648, AKT, temozolomide

Received: September 22, 2015    Accepted: June 29, 2016    Published: July 27, 2016

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.


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