title: Targeting hyperactivated DNA-PKcs by KU0060648 inhibits glioma progression and enhances temozolomide therapy via suppression of AKT signaling.
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.
authors.affiliation: 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.
authors.forename: Tian
authors.initials: T
authors.lastname: Lan
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Zitong
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China.
authors.forename: Mingshan
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China.
authors.forename: Haoran
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China.
authors.forename: Chunjiang
authors.initials: C
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Qimin
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Song
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D051747:DNA-Activated Protein Kinase; D051057:Proto-Oncogene Proteins c-akt; D000077204:Temozolomide
keywords: AKT; KU0060648; glioma; p-DNA-PKcs; temozolomide