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

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

doi:10.18632/oncotarget.10864

Cited by 19 publications

(18 citation statements)

References 62 publications

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“…5b), suggesting MCM3 knockdown reduced radioresistance. DNA-PKcs activation is critical for development of tumor therapy resistance [34, 35], cleaved PARP1 is a marker for apoptosis [36], we isolated tumors from mice, western blot assay showed that MCM3 knockdown inhibited the phosphorylation of DNA-PKcs, and increased PARP1 cleavage (Fig. 5c), suggesting MCM3 knockdown reduced radioresistance.…”

Section: Resultsmentioning

confidence: 99%

Minichromosome maintenance 3 promotes hepatocellular carcinoma radioresistance by activating the NF-κB pathway

Yang

Xie

Tang

et al. 2019

J Exp Clin Cancer Res

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Background Hepatocellular carcinoma (HCC) is the most common tumors in the worldwide, it develops resistance to radiotherapy during treatment, understanding the regulatory mechanisms of radioresistance generation is the urgent need for HCC therapy. Methods qRT-PCR, western blot and immunohistochemistry were used to examine MCM3 expression. MTT assay, colony formation assay, terminal deoxynucleotidyl transferase nick end labeling assay and In vivo xenograft assay were used to determine the effect of MCM3 on radioresistance . Gene set enrichment analysis, luciferase reporter assay, western blot and qRT-PCR were used to examine the effect of MCM3 on NF-κB pathway. Results We found DNA replication initiation protein Minichromosome Maintenance 3 (MCM3) was upregulated in HCC tissues and cells, patients with high MCM3 expression had poor outcome, it was an independent prognostic factor for HCC. Cells with high MCM3 expression or MCM3 overexpression increased the radioresistance determined by MTT assay, colony formation assay, TUNEL assay and orthotopic transplantation mouse model, while cells with low MCM3 expression or MCM3 knockdown reduced the radioresistance. Mechanism analysis showed MCM3 activated NF-κB pathway, characterized by increasing the nuclear translocation of p65, the expression of the downstream genes NF-κB pathway and the phosphorylation of IKK-β and IκBα. Inhibition of NF-κB in MCM3 overexpressing cells using small molecular inhibitor reduced the radioresistance, suggesting MCM3 increased radioresistance through activating NF-κB pathway. Moreover, we found MCM3 expression positively correlated with NF-κB pathway in clinic. Conclusions Our findings revealed that MCM3 promoted radioresistance through activating NF-κB pathway, strengthening the role of MCM subunits in the tumor progression and providing a new target for HCC therapy. Electronic supplementary material The online version of this article (10.1186/s13046-019-1241-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Minichromosome maintenance 3 promotes hepatocellular carcinoma radioresistance by activating the NF-κB pathway

Yang

Xie

Tang

et al. 2019

J Exp Clin Cancer Res

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“…Both Mo59K and U-87 MG have been shown to express high levels of activated DNA-PKcs (i.e. p-DNA-PKcs) in contrast to both normal human astrocyte cells and also the glioma cell lines A172 and H4 [17].…”

Section: Differences In Response Based Upon Cell Typementioning

confidence: 99%

Cytotoxicity, dose-enhancement and radiosensitization of glioblastoma cells with rare earth nanoparticles

Crawshay-Williams

White

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Glioblastoma is a heterogeneous disease with multiple genotypic origins. Despite treatment protocols such as surgery, radiotherapy and chemotherapy, the prognosis for patients remains poor. This study investigates the cytotoxic and radiation dose-enhancing and radiosensitizing ability of five rare earth oxide nanoparticles, in two different immortalized mammalian cell lines; U-87 MG and Mo59K. Significant cytotoxicity was observed in U-87 MG cells when exposed to Nd 2 O 3 and La 2 O 3. Autophagy was also detected in cells after incubation with Nd 2 O 3. Radiosensitization was observed in U-87 MG when incubated with Gd 2 O 3 , CeO 2-Gd and Nd 2 O 3 :Si. Importantly, these elements did not cause any intrinsic toxicity in the absence of irradiation and so could be considered biocompatible. The Gd 2 O 3 and CeO 2-Gd nanoparticles were also seen to generate ROS in U-87 MG cells after irradiation. Furthermore, the Mo59K and U-87 MG cells responded very differently to exposure to the rare earth nanoparticles. This may indicate the importance of the genotype of cells in the successful use of rare earth oxides for treatment.

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“…Phospho-DNA-PK expression is significantly higher in human glioma than their respective adjacent non-tumorous tissue and correlates with malignant development and poor prognosis in glioma patients. 27 A recent transcriptome analysis identified DNA-PK as a predominant DNA repair enzyme in glioma stem cells (GSCs), which drives radiation resistance in GBM. 28 …”

Section: Dna-pk Inhibitorsmentioning

confidence: 99%

The promise of DNA damage response inhibitors for the treatment of glioblastoma

Majd

Yap

Koul

et al. 2021

Neuro-Oncology Advances

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Glioblastoma (GBM), the most aggressive primary brain tumor, has a dismal prognosis. Despite our growing knowledge of genomic and epigenomic alterations in GBM, standard therapies and outcomes have not changed significantly in the past two decades. There is therefore an urgent unmet need to develop novel therapies for GBM. The inter- and intra-tumoral heterogeneity of GBM, inadequate drug concentrations in the tumor owing to the blood-brain barrier, redundant signaling pathways contributing to resistance to conventional therapies, and an immunosuppressive tumor microenvironment, have all hindered the development of novel therapies for GBM. Given the high frequency of DNA damage pathway alterations in GBM, researchers have focused their efforts on pharmacologically targeting key enzymes, including poly(ADP-ribose) polymerase (PARP), DNA-dependent protein kinase, ataxia telangiectasia-mutated, and ataxia telangiectasia and Rad3-related. The mainstays of GBM treatment, ionizing radiation and alkylating chemotherapy, generate DNA damage that is repaired through the upregulation and activation of DNA damage response (DDR) enzymes. Therefore, the use of PARP and other DDR inhibitors to render GBM cells more vulnerable to conventional treatments is an area of intense investigation. In this review, we highlight the growing body of data behind DDR inhibitors in GBM, with a focus on putative predictive biomarkers of response. We also discuss the challenges involved in the successful development of DDR inhibitors for GBM, including the intracranial location and predicted overlapping toxicities of DDR agents with current standards of care, and propose promising strategies to overcome these hurdles.

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

Cited by 19 publications

References 62 publications

Minichromosome maintenance 3 promotes hepatocellular carcinoma radioresistance by activating the NF-κB pathway

Minichromosome maintenance 3 promotes hepatocellular carcinoma radioresistance by activating the NF-κB pathway

Cytotoxicity, dose-enhancement and radiosensitization of glioblastoma cells with rare earth nanoparticles

The promise of DNA damage response inhibitors for the treatment of glioblastoma

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