DNA-PK in human malignant disorders: Mechanisms and implications for pharmacological interventions

Medová, Michaela; Medo, Matúš; Hovhannisyan, Lusine; Muñoz-Maldonado, Carmen; Aebersold, Daniel M.; Zimmer, Yitzhak

doi:10.1016/j.pharmthera.2020.107617

Cited by 33 publications

(30 citation statements)

References 233 publications

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“…Overexpression of ATM has been associated with lymph node metastasis, while inhibition of ATM has been described to reduce cell migration and invasion [ 61 ]. Similar findings have been obtained for DNA-PK and its inhibition [ 62 , 63 ]. Interestingly, other factors involved in DNA-DSB repair such as the oncogene PP4R1 and Rad51 are also known for facilitating the formation of metastases when upregulated or overexposed and can be regulated with inhibitors [ 64 , 65 ].…”

Section: Discussionsupporting

confidence: 89%

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

Faulhaber

Jost

Symank

et al. 2021

Genes

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(1) Kinase inhibitors (KI) targeting components of the DNA damage repair pathway are a promising new type of drug. Combining them with ionizing radiation therapy (IR), which is commonly used for treatment of head and neck tumors, could improve tumor control, but could also increase negative side effects on surrounding normal tissue. (2) The effect of KI of the DDR (ATMi: AZD0156; ATRi: VE-822, dual DNA-PKi/mTORi: CC-115) in combination with IR on HPV-positive and HPV-negative HNSCC and healthy skin cells was analyzed. Cell death and cell cycle arrest were determined using flow cytometry. Additionally, clonogenic survival and migration were analyzed. (3) Studied HNSCC cell lines reacted differently to DDRi. An increase in cell death for all of the malignant cells could be observed when combining IR and KI. Healthy fibroblasts were not affected by simultaneous treatment. Migration was partially impaired. Influence on the cell cycle varied between the cell lines and inhibitors; (4) In conclusion, a combination of DDRi with IR could be feasible for patients with HNSCC. Side effects on healthy cells are expected to be limited to normal radiation-induced response. Formation of metastases could be decreased because cell migration is impaired partially. The treatment outcome for HPV-negative tumors tends to be improved by combined treatment.

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Section: Discussionsupporting

confidence: 89%

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

Faulhaber

Jost

Symank

et al. 2021

Genes

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“…In addition, TSPOAP1 and TSPO mediate the activity of CREB1, a transcription factor, which promotes cell proliferation and differentiation via association with cAMP response element modulatory protein (Crem) and activating transcription factor 1 (Atf1) ( Antony et al, 2016 ; Friedrich et al, 2020 ). DNA-PK is a serine/threonine protein kinase, which acts as a molecular sensor against DNA damage and repairs it ( Medová et al, 2020 ). Abnormal expression and deregulation of DNA-PK lead to inflammatory disorders and cancer ( Medová et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…DNA-PK is a serine/threonine protein kinase, which acts as a molecular sensor against DNA damage and repairs it ( Medová et al, 2020 ). Abnormal expression and deregulation of DNA-PK lead to inflammatory disorders and cancer ( Medová et al, 2020 ). TSPOAP1 and TSPOP alter the response of DNA-PK against DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic Analyses of Canonical Pathways of TSPOAP1 and its Roles in Human Diseases

Kumar

Alam

Lee

et al. 2021

Front. Mol. Biosci.

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TSPO-associated protein 1 (TSPOAP1) is a cytoplasmic protein and is closely associated with its mitochondrial transmembrane protein partner translocator protein (TSPO). To decipher the canonical signalling pathways of TSPOAP1, its role in human diseases and disorders, and relationship with TSPO; expression analyses of TSPOAP1- and TSPO-associated human genes were performed by Qiagen Ingenuity Pathway Analysis (IPA). In the expression analysis, necroptosis and sirtuin signalling pathways, mitochondrial dysfunction, and inflammasome were the top canonical pathways for both TSPOAP1 and TSPO, confirming the close relationship between these two proteins. A distribution analysis of common proteins in all the canonical pathways predicted for TSPOAP1 revealed that tumor necrosis factor receptor 1 (TNFR1), vascular cell adhesion molecule 1 (VCAM1), cyclic AMP response element-binding protein 1 (CREB1), T-cell receptor (TCR), nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NLRP3), DNA-dependent protein kinase (DNA-PK or PRKDC), and mitochondrial permeability transition pore (mPTP) were the major interaction partners of TSPOAP1, highlighting the role of TSPOAP1 in inflammation, particularly neuroinflammation. An analysis of the overlap between TSPO and TSPOAP1 Homo sapiens genes and top-ranked canonical pathways indicated that TSPO and TSPOAP1 interact via voltage-dependent anion-selective channels (VDAC1/2/3). A heat map analysis indicated that TSPOAP1 has critical roles in inflammatory, neuroinflammatory, psychiatric, and metabolic diseases and disorders, and cancer. Taken together, this information improves our understanding of the mechanism of action and biological functions of TSPOAP1 as well as its relationship with TSPO; furthermore, these results could provide new directions for in-depth functional studies of TSPOAP1 aimed at unmasking its detailed functions.

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“…DNA-dependent protein kinase has become an attractive therapeutic target in various cancer treatments, especially when used in combination with genotoxic chemotherapy or ionizing radiation (Huang and Zhou, 2020;Medová et al, 2020). Studies have shown that targeting DNA-PKcs with various inhibitors can effectively enhance radiotherapy, and many small molecule inhibitors of DNA-PKcs have been developed and shown to be effective radiosensitizers in vitro ( Table 2).…”

Section: Targeting Dna-pkcs To Reprogram the Cellular Radiosensitivitymentioning

confidence: 99%

DNA-PKcs: A Multi-Faceted Player in DNA Damage Response

et al. 2020

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DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a member of the phosphatidylinositol 3-kinase related kinase family, which can phosphorylate more than 700 substrates. As the core enzyme, DNA-PKcs forms the active DNA-PK holoenzyme with the Ku80/Ku70 heterodimer to play crucial roles in cellular DNA damage response (DDR). Once DNA double strand breaks (DSBs) occur in the cells, DNA-PKcs is promptly recruited into damage sites and activated. DNA-PKcs is auto-phosphorylated and phosphorylated by Ataxia-Telangiectasia Mutated at multiple sites, and phosphorylates other targets, participating in a series of DDR and repair processes, which determine the cells’ fates: DSBs NHEJ repair and pathway choice, replication stress response, cell cycle checkpoints, telomeres length maintenance, senescence, autophagy, etc. Due to the special and multi-faceted roles of DNA-PKcs in the cellular responses to DNA damage, it is important to precisely regulate the formation and dynamic of its functional complex and activities for guarding genomic stability. On the other hand, targeting DNA-PKcs has been considered as a promising strategy of exploring novel radiosensitizers and killing agents of cancer cells. Combining DNA-PKcs inhibitors with radiotherapy can effectively enhance the efficacy of radiotherapy, offering more possibilities for cancer therapy.

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DNA-PK in human malignant disorders: Mechanisms and implications for pharmacological interventions

Cited by 33 publications

References 233 publications

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

Bioinformatic Analyses of Canonical Pathways of TSPOAP1 and its Roles in Human Diseases

DNA-PKcs: A Multi-Faceted Player in DNA Damage Response

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