High expression of VRK1 is related to poor prognosis in glioma

Ben, Zhiyun; Gong, Leilei; Qiu, Yue

doi:10.1016/j.prp.2017.10.014

Cited by 27 publications

(55 citation statements)

References 25 publications

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“…Furthermore, targeting VRK1 can also have additional effects on tumor progression. High levels of VRK1 has been associated as a bad prognostic indicator to several tumors such as breast [27, 61, 62], gliomas [28], colon [63], lung [47, 64], and hepatocarcinomas [30] among others. Mechanistically, these high VRK1 levels facilitate tumor cell proliferation [22, 45, 65], metastasis formation [66], and resistance to DNA damage [20, 26] mediated by the activation of repair process in chromatin [19] and by p53-mediated responses [52, 55, 56, 67, 68].…”

Section: Discussionmentioning

confidence: 99%

Olaparib and ionizing radiation trigger a cooperative DNA-damage repair response that is impaired by depletion of the VRK1 chromatin kinase

Campillo-Marcos

Lazo

2019

J Exp Clin Cancer Res

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Background The VRK1 chromatin kinase regulates the organization of locally altered chromatin induced by DNA damage. The combination of ionizing radiation with inhibitors of DNA damage responses increases the accumulation of DNA damage in cancer cells, which facilitates their antitumor effect, a process regulated by VRK1. Methods Tumor cell lines with different genetic backgrounds were treated with olaparib to determine their effect on the activation of DNA repair pathways induced by ionizing radiation. The effect of combining olaparib with depletion of the chromatin kinase VRK1 was studied in the context of double-strand breaks repair pathway after treatment with ionizing radiation. The initiation and progression of DDR were studied by specific histone acetylation, as a marker of local chromatin relaxation, and formation of γH2AX and 53BP1 foci. Results In this work, we have studied the effect that VRK1 by itself or in collaboration with olaparib, an inhibitor of PARP, has on the DNA oxidative damage induced by irradiation in order to identify its potential as a new drug target. The combination of olaparib and ionizing radiation increases DNA damage permitting a significant reduction of their respective doses to achieve a similar amount of DNA damage detected by γH2AX and 53BP1 foci. Different treatment combinations of olaparib and ionizing radiation permitted to reach the maximum level of DNA damage at lower doses of both treatments. Furthermore, we have studied the effect that depletion of the VRK1 chromatin kinase, a regulator of DDR, has on this response. VRK1 knockdown impaired all steps in the DDR induced by these treatments, which were detected by a reduction of sequential markers such as H4K16 ac, γH2AX, NBS1 and 53BP1. Moreover, this effect of VRK1 is independent of TP53 or ATM , two genes frequently mutated in cancer. Conclusion The protective DNA damage response induced by ionizing radiation is impaired by the combination of olaparib with depletion of VRK1, and can be used to reduce doses of radiation and their associated toxicity. Proteins implicated in DNA damage responses are suitable targets for development of new therapeutic strategies and their combination can be an alternative form of synthetic lethality. Electronic supplementary material The online version of this article (10.1186/s13046-019-1204-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Olaparib and ionizing radiation trigger a cooperative DNA-damage repair response that is impaired by depletion of the VRK1 chromatin kinase

Campillo-Marcos

Lazo

2019

J Exp Clin Cancer Res

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“…VRK1 might act as an important cell cycle regulator contributing to a poorer tumor prognosis [ 12 ]. In HCC [ 26 ] and glioma [ 29 ], its depletion by siRNAs induces a stop in the G1 phase. These results were obtained with our data ( Figure 4 C) demonstrating that our aptamers are able to inhibit cell cycle progression in G1-S phase transition.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, several studies have suggested the involvement of VRK1 overexpression and its correlation with poor prognosis in many cancer types such as head and neck squamous cell carcinoma (HNSCC) [ 24 ], lung cancer [ 25 ], hepatocellular carcinoma (HCC) [ 26 , 27 ], esophageal cancer [ 28 ], glioma [ 29 ] or breast cancer [ 30 ]. Regarding the latter, VRK1 could promote cancer cell colonization by enhancing the mesenchymal-to-epithelial transition (MET) via downregulating the expression of mesenchymal markers and upregulating that of epithelial markers, which associates VRK1 with breast cancer progression [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

DNA Aptamers against Vaccinia-Related Kinase (VRK) 1 Block Proliferation in MCF7 Breast Cancer Cells

et al. 2021

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Vaccinia-related kinase (VRK) 1 is a serin/threonine kinase that plays an important role in DNA damage response (DDR), phosphorylating some proteins involved in this process such as 53BP1, NBS1 or H2AX, and in the cell cycle progression. In addition, VRK1 is overexpressed in many cancer types and its correlation with poor prognosis has been determined, showing VRK1 as a new therapeutic target in oncology. Using in vitro selection, high-affinity DNA aptamers to VRK1 were selected from a library of ssDNA. Selection was monitored using the enzyme-linked oligonucleotide assay (ELONA), and the selected aptamer population was cloned and sequenced. Three aptamers were selected and characterized. These aptamers recognized the protein kinase VRK1 with an affinity in the nanomolar range and showed a high sensibility. Moreover, the treatment of the MCF7 breast cell line with these aptamers resulted in a decrease in cyclin D1 levels, and an inhibition of cell cycle progression by G1 phase arrest, which induced apoptosis in cells. These results suggest that these aptamers are specific inhibitors of VRK1 that might be developed as potential drugs for the treatment of cancer.

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“…7−11 VRK1 overexpression is associated with increased cell division and poor prognosis in a number of cancers. 12,13 Despite these advances, our understanding of the cellular roles of human VRKs and their therapeutic potential is limited. Currently, there are no potent and specific small molecule inhibitors of the VRKs.…”

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confidence: 99%

Development of Pyridine-based Inhibitors for the Human Vaccinia-related Kinases 1 and 2

Serafim

Gama²,

Dutra

et al. 2019

ACS Med. Chem. Lett.

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Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no potent and specific inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compound for VRK1 (26) displayed an IC50 value of 150 nM and was fairly selective in a panel of 48 human kinases (selectivity score S(50%) of 0.04). Differences in compound binding mode and substituent preferences between the two VRKs were identified by the structure−activity relationship combined with the crystallographic analysis of key compounds. We expect our results to serve as a starting point for the design of more specific and potent inhibitors against each of the two VRKs.

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High expression of VRK1 is related to poor prognosis in glioma

Cited by 27 publications

References 25 publications

Olaparib and ionizing radiation trigger a cooperative DNA-damage repair response that is impaired by depletion of the VRK1 chromatin kinase

Olaparib and ionizing radiation trigger a cooperative DNA-damage repair response that is impaired by depletion of the VRK1 chromatin kinase

DNA Aptamers against Vaccinia-Related Kinase (VRK) 1 Block Proliferation in MCF7 Breast Cancer Cells

Development of Pyridine-based Inhibitors for the Human Vaccinia-related Kinases 1 and 2

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