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.
Highlights
Characterized by a median survival ranging from 5 to 59 months and accounting for 70% of adult primary central nervous system tumors, glioma has been regarded as the most deadly brain malignancy that is essentially incurable [1, 2]
We reported that the p-DNAPKcs (S2056) was significantly elevated in glioma compared with adjacent normal brain, and such a high level of phosphorylated DNA-PKcs tightly associated with malignancy of glioma, including clinical stage www.impactjournals.com/oncotarget and the survival time of glioma patients, collectively demonstrating a pivotal role of DNA-PKcs in the progression of glioma
The results indicated that inhibition of DNA-PKcs activation decreased glioma cell malignancies and promoted TMZ efficacy
Summary
Characterized by a median survival ranging from 5 to 59 months and accounting for 70% of adult primary central nervous system tumors, glioma has been regarded as the most deadly brain malignancy that is essentially incurable [1, 2]. Drug resistance restricts the clinical application of TMZ and contributes to the dismal outcome of glioma patient [5, 6]. This challenging problem attributes to multitudes of aberrant molecular changes, such as MGMT promoter methylation, α5β1 integrin expression, sonic hedgehog and notch pathway activation [7,8,9,10]. We surveyed the p-DNA-PKcs (Ser 2056) level in human glioma samples and observed that hyperactivation of DNA-PKcs was closely associated with both malignant progression and poor clinical outcome of glioma patients. This study provides a potential target for evaluating glioma progression and improving TMZ efficacy in glioma therapy
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