Temporal DNA-PK activation drives genomic instability and therapy resistance in glioma stem cells

Wang, Yanling; Xu, Haineng; Liu, Tianrun; Huang, Menggui; Butter, Param-Puneet; Li, Chunsheng; Zhang, Lin; Kao, Gary D.; Gong, Yanqing; Maity, Amit; Koumenis, Constantinos; Fan, Yi

doi:10.1172/jci.insight.98096

Cited by 47 publications

(38 citation statements)

References 59 publications

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“…The anti-CD133 mAbs were determined to be useful for every application, including for flow cytometry, western blot, and immunohistochemical analyses. While there are several anti-CD133 mAbs are commercially available, the applications of those mAbs are usually limited (19); therefore, we have to use several mAbs or polyclonal antibodies for different experimental procedures.…”

Section: Discussionmentioning

confidence: 99%

Establishment of C20Mab‑11, a novel anti‑CD20 monoclonal antibody, for the detection of B cells

2020

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CD20 is one of several B-lymphocyte antigens that has been shown to be an effective target for the detection and treatment of B-cell lymphomas. Sensitive and specific monoclonal antibodies (mAbs) are required for every application used for the diagnosis of B-cell lymphoma. Although many anti-CD20 mAbs have been established, the types of applications, those anti-CD20 can be used in, are limited. In this study, we aimed to establish novel anti-CD20 mAbs to be used for broad applications, such as flow cytometry, western blot, and immunohistochemical analyses, using the Cell-Based Immunization and Screening (CBIS) method. One of the established mAbs, C 20 Mab-11 (IgM, kappa), detected overexpression of CD20 in CHO-K1 or LN229 cell lines, indicating that C 20 Mab-11 is specific for CD20. In western blot analyses, C 20 Mab-11 detected not only overexpression of CD20 in CHO-K1 or LN229 cell lines, but also CD20 of BALL-1 and Raji cells with both sensitivity and specificity. Furthermore, C 20 Mab-11 strongly stained B cells of the lymph follicle and B cell lymphomas in immunohistochemical analyses. These results indicate that C 20 Mab-11 develped by CBIS method, is useful for the detection of CD20 in lymphoma tissues by flow cytometry, western blot, and immunohistochemical analyses and potentially could be beneficial for the treatment of B cell lymphomas.

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Section: Discussionmentioning

confidence: 99%

Establishment of C20Mab‑11, a novel anti‑CD20 monoclonal antibody, for the detection of B cells

2020

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“…Increasing evidence has suggested that rapid acquired therapeutic resistance is the major cause of the failure of standard comprehensive treatments, leading to the recurrence and high mortality of glioma . Various molecular pathways have been shown to be responsible for the acquisition of therapeutic resistance in glioma . Therefore, it is essential to identify the mechanisms, especially prognostic biomarkers, underlying therapeutic resistance in glioma.…”

Section: Discussionmentioning

confidence: 99%

“…29,30 Various molecular pathways have been shown to be responsible for the acquisition of therapeutic resistance in glioma. 26,[31][32][33] Therefore, it is essential to identify the mechanisms, especially prognostic biomarkers, underlying therapeutic resistance in glioma. In this study, we analyzed the transcriptome expression profiles of 3 published GEO databases related to pathological classification, radioresistance, and TMZ resistance and identified TRIB2…”

Section: Discussionmentioning

confidence: 99%

Combined elevation of TRIB2 and MAP3K1 indicates poor prognosis and chemoresistance to temozolomide in glioblastoma

et al. 2019

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Introduction Glioblastoma (GBM) is the most lethal primary malignant brain tumor in adults with poor survival due to acquired therapeutic resistance and rapid recurrence. Currently, the standard clinical strategy for glioma includes maximum surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy; however, the median survival of patients with GBM remains poor despite these comprehensive therapies. Therefore, the identification of new prognostic biomarkers is urgently needed to evaluate the malignancy and long‐term outcome of glioma. Aims To further investigate prognostic biomarkers and potential therapeutic targets for GBM. Results In this study, we identified tribbles pseudokinase 2 (TRIB2) as one of the genes that is most correlated with pathological classification, radioresistance, and TMZ resistance in glioma. Additionally, the expression of mitogen‐activated protein kinase kinase kinase 1 (MAP3K1) showed a strong correlation with TRIB2. Moreover, a combined increase in TRIB2 and MAP3K1 was observed in GBM and indicated a poor prognosis of patients with glioma. Finally, enriched TRIB2 expression and MAP3K1 expression were shown to be associated with resistance to TMZ and radiotherapy. Conclusion Combined elevation of TRIB2 and MAP3K1 could be novel prognostic biomarkers and potential therapeutic targets to evaluate the malignancy and long‐term outcomes of GBM.

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“…Hypoxic tumours are known to have higher infiltration of pro-tumour immune cells such as M2 macrophages 35 , a feature known to be involved in RR 36 , 37 . The same could also be said with respect to the hypoxic-induction of highly RT resistant cancer stem cells 38 . Though this subject needs further research, the likelihood of an interplay between intracellular genetic reprogramming as a result of hypoxic adaption and the microenvironment in mediating radioresponse is strong.…”

Section: The Landscape Of the Hypoxic Tumourmentioning

confidence: 99%

Inside the hypoxic tumour: reprogramming of the DDR and radioresistance

Begg

Tavassoli

2020

Cell Death Discov.

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The hypoxic tumour is a chaotic landscape of struggle and adaption. Against the adversity of oxygen starvation, hypoxic cancer cells initiate a reprogramming of transcriptional activities, allowing for survival, metastasis and treatment failure. This makes hypoxia a crucial feature of aggressive tumours. Its importance, to cancer and other diseases, was recognised by the award of the 2019 Nobel Prize in Physiology or Medicine for research contributing to our understanding of the cellular response to oxygen deprivation. For cancers with limited treatment options, for example those that rely heavily on radiotherapy, the results of hypoxic adaption are particularly restrictive to treatment success. A fundamental aspect of this hypoxic reprogramming with direct relevance to radioresistance, is the alteration to the DNA damage response, a complex set of intermingling processes that guide the cell (for good or for bad) towards DNA repair or cell death. These alterations, compounded by the fact that oxygen is required to induce damage to DNA during radiotherapy, means that hypoxia represents a persistent obstacle in the treatment of many solid tumours. Considerable research has been done to reverse, correct or diminish hypoxia’s power over successful treatment. Though many clinical trials have been performed or are ongoing, particularly in the context of imaging studies and biomarker discovery, this research has yet to inform clinical practice. Indeed, the only hypoxia intervention incorporated into standard of care is the use of the hypoxia-activated prodrug Nimorazole, for head and neck cancer patients in Denmark. Decades of research have allowed us to build a picture of the shift in the DNA repair capabilities of hypoxic cancer cells. A literature consensus tells us that key signal transducers of this response are upregulated, where repair proteins are downregulated. However, a complete understanding of how these alterations lead to radioresistance is yet to come.

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Temporal DNA-PK activation drives genomic instability and therapy resistance in glioma stem cells

Cited by 47 publications

References 59 publications

Establishment of C20Mab‑11, a novel anti‑CD20 monoclonal antibody, for the detection of B cells

Establishment of C20Mab‑11, a novel anti‑CD20 monoclonal antibody, for the detection of B cells

Combined elevation of TRIB2 and MAP3K1 indicates poor prognosis and chemoresistance to temozolomide in glioblastoma

Inside the hypoxic tumour: reprogramming of the DDR and radioresistance

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