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

Carrión-Marchante, Rebeca; Frezza, Valerio; Salgado-Figueroa, Ana; Pérez-Morgado, M. Isabel; Martı́n, M. Elena; González, Víctor

doi:10.3390/ph14050473

“…Previously, it was shown that VRK1 expression could promote cell proliferation in myeloma by regulating cell cycle-related proteins [18]. Te current study found that the inhibition of LUSC cell proliferation was due to depletion of VRK1, which induces the cell cycle arrest in the G0/G1 phase, which is also consistent with Carrion-Marchante et al [19]. VRK1 promotes cell proliferation and migration in gastric cancer cells [14], esophageal squamous cell carcinoma [20], bladder cancer [21], and we derived the same results in LUSC.…”

Section: Discussionsupporting

confidence: 91%

Downregulation of VRK1 Inhibits Progression of Lung Squamous Cell Carcinoma through DNA Damage

Du

¹

,

Zhang

²

,

Zhang

³

2023

Canadian Respiratory Journal

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Background. Lung squamous cell carcinoma (LUSC) is a common malignancy. And the antitumor effect of bovine pox virus-associated kinase 1 (VRK1) is becoming a hot research topic. Methods. VRK1 expression and prognosis in LUSC were analyzed using the GEPIA database. The expression of VRK1 mRNA was detected in 25 LUSC clinical tissue samples by RT-PCR. VRK1 shRNA was transfected into LUSC NCI-H520 and SK-MES-1 cell lines to interfere with VRK1 expression, and the efficiency of VRK1 shRNA interference was detected by the western blot. The effects of VRK1 downregulation on LUSC cell viability, migration, cell cycle, and apoptosis were analyzed by the CCK8 assay, scratch assay, transwell assay, and flow cytometry. The effect of VRK1 downregulation on DNA damage response (DDR) was examined by immunofluorescence staining and western blot assays and further validated by in vivo experiments. Results. VRK1 was highly expressed in both LUSC tissues and cells. Survival analysis showed that the overall survival of LUSC patients with high VRK1 expression was significantly lower than that of LUSC patients with low VRK1 expression ( P = 0.0026 ). The expression level of the VRK1 gene was significantly higher in cancer tissues of LUSC patients than in paracancerous tissues. After transfection of VRK1 shRNA in both LUSC cells, cell activity decreased ( P < 0.001 ), migration ability started to be inhibited ( P < 0.001 ), the ratio of G0/G1 phase cells increased ( P < 0.001 ), and apoptosis rate increased ( P < 0.001 ). Immunofluorescence and western blot results showed that shVRK1 increased the level of γ-H2A.X ( P < 0.001 ) and promoted apoptosis of tumor cells ( P < 0.001 ). In addition, the results of animal experiments showed that shVRK1 had antitumor effects ( P < 0.001 ) and a combined effect with DOX ( P < 0.001 ). Conclusion. The downregulation of VRK1 significantly affected the proliferation, apoptosis, migration, and cell cycle progression of LUSC cells via DDR, suggesting that VRK1 is a suitable target for potential LUSC therapy.

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“…In cancer cells, VRK activates TNFα/NF‐κB signaling by phosphorylating IKKβ, and regulates cell cycle and DNA damage response (Figure 8 ). 224 , 225 It was demonstrated that VRK2 is a specific therapeutic target, and its inhibitor combined with PD‐1 blockade may be effective in improving immunotherapy in patients with cancers. 226 …”

Section: Kinase Groupsmentioning

confidence: 99%

“…In cancer cells, VRK activates TNFα/NF-κB signaling by phosphorylating IKKβ, and regulates cell cycle and DNA damage response (Figure 8). 224,225 It was demonstrated that VRK2 is a specific therapeutic target, and its inhibitor combined with PD-1 blockade may be effective in improving immunotherapy in patients with cancers. 226 2.8.4 DNA-dependent protein kinase DNA-dependent protein kinase (DNA-PK) is a type of kinase that phosphorylates nuclear DNA helicase II/RNA helicase A and hnRNP proteins in an RNA-dependent manner.…”

Section: Ck1-vrk Familymentioning

confidence: 99%

Role of protein phosphorylation in cell signaling, disease, and the intervention therapy

Pang

¹

,

Wang

²

,

Qin

³

et al. 2022

MedComm

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Protein phosphorylation is an important post‐transcriptional modification involving an extremely wide range of intracellular signaling transduction pathways, making it an important therapeutic target for disease intervention. At present, numerous drugs targeting protein phosphorylation have been developed for the treatment of various diseases including malignant tumors, neurological diseases, infectious diseases, and immune diseases. In this review article, we analyzed 303 small‐molecule protein phosphorylation kinase inhibitors (PKIs) registered and participated in clinical research obtained in a database named Protein Kinase Inhibitor Database (PKIDB), including 68 drugs approved by the Food and Drug Administration of the United States. Based on previous classifications of kinases, we divided these human protein phosphorylation kinases into eight groups and nearly 50 families, and delineated their main regulatory pathways, upstream and downstream targets. These groups include: protein kinase A, G, and C (AGC) and receptor guanylate cyclase (RGC) group, calmodulin‐dependent protein kinase (CaMK) group, CMGC [Cyclin‐dependent kinases (CDKs), Mitogen‐activated protein kinases (MAPKs), Glycogen synthase kinases (GSKs), and C dc2‐like kinases (CLKs)] group, sterile (STE)‐MAPKs group, tyrosine kinases (TK) group, tyrosine kinase‐like (TKL) group, atypical group, and other groups. Different groups and families of inhibitors stimulate or inhibit others, forming an intricate molecular signaling regulatory network. This review takes newly developed new PKIs as breakthrough point, aiming to clarify the regulatory network and relationship of each pathway, as well as their roles in disease intervention, and provide a direction for future drug development.

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“…Molecules directed against BAF1 or VRK1 are actively searched as anticancer agents. For examples, DNA aptamers targeting specifically VRK1 were found to efficiently block proliferation of MCF7 breast cancer cells ( Carrión-Marchante et al., 2021 ). Various small molecules selectively targeting VRK1 have also been identified and designed ( Couñago et al., 2017 ; Serafim et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Interaction of obtusilactone B and related butanolide lactones with the barrier-to-autointegration factor 1 (BAF1). A computational study

Bailly

¹

,

Vergoten

²

2021

Current Research in Pharmacology and Drug Discovery

3

0

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The barrier-to-autointegration factor 1 (BAF1) protein is a DNA-binding protein implicated in nuclear envelop repair and reformation after mitosis. This nuclear protein is frequently overexpressed in cancer cells and plays a role in the occurrence and development of different tumors. It is a potential therapeutic target for gastric cancer, breast cancer and other malignancies. For this reason, BAF1 inhibitors are searched. The butanolide lactone obtusilactone B (Ob-B) has been found to inhibit VRK1-dependent phosphorylation of BAF1, upon direct binding to the nuclear protein. Taking advantage of the known crystallographic structure of BAF1, we have elaborated molecular models of Ob-B bound to BAF1 to delimit the binding site and binding configuration. The long endoolefinic alkyl side chain of Ob-B extends into a small groove on the protein surface, and the adjacent exomethylene-γ-lactone moiety occupies a pocket comprising to the Ser-4 phosphorylation site of BAF1. Twenty butanolide lactones structurally close to ObB were screened for BAF1 binding. Several natural products with BAF1-binding capacity potentially superior to Ob-B were identified, including mahubanolide, kotomolide B, epilitsenolide D2, and a few other known anticancer plant natural products. Our study provides new ideas to guide the discovery and design of BAF1 inhibitors.

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

Cited by 9 publications

References 52 publications

Downregulation of VRK1 Inhibits Progression of Lung Squamous Cell Carcinoma through DNA Damage

Downregulation of VRK1 Inhibits Progression of Lung Squamous Cell Carcinoma through DNA Damage

Role of protein phosphorylation in cell signaling, disease, and the intervention therapy

Interaction of obtusilactone B and related butanolide lactones with the barrier-to-autointegration factor 1 (BAF1). A computational study

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