scholarly journals CSNK2 in cancer: pathophysiology and translational applications

2021 ◽  
Author(s):  
Scott W. Strum ◽  
Laszlo Gyenis ◽  
David W. Litchfield
Keyword(s):  
Human Cancer ◽  
Cell Cycle Control ◽  
Prognostic Significance ◽  
Hematologic Malignancies ◽  
Protein Levels ◽  
Wide Range ◽  
Positive Treatment ◽  
Extensive Body

AbstractProtein kinase CSNK2 (CK2) is a pleiotropic serine/threonine kinase frequently dysregulated in solid and hematologic malignancies. To consolidate a wide range of biological and clinically oriented data from this unique kinase in cancer, this systematic review summarises existing knowledge from in vitro, in vivo and pre-clinical studies on CSNK2 across 24 different human cancer types. CSNK2 mRNA transcripts, protein levels and activity were found to be routinely upregulated in cancer, and commonly identified phosphotargets included AKT, STAT3, RELA, PTEN and TP53. Phenotypically, it frequently influenced evasion of apoptosis, enhancement of proliferation, cell invasion/metastasis and cell cycle control. Clinically, it held prognostic significance across 14 different cancers, and its inhibition in xenograft experiments resulted in a positive treatment response in 12. In conjunction with commentary on preliminary studies of CSNK2 inhibitors in humans, this review harmonises an extensive body of CSNK2 data in cancer and reinforces its emergence as an attractive target for cancer therapy. Continuing to investigate CSNK2 will be crucial to advancing our understanding of CSNK2 biology, and offers the promise of important new discoveries scientifically and clinically.

CSNK2 in cancer: Pathophysiology and translational applications.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15594-e15594
Author(s):  
Scott Strum ◽  
Laszlo Gyenis ◽  
David W Litchfield
Keyword(s):  
Current Knowledge ◽  
Human Cancer ◽  
Prognostic Significance ◽  
Response To Treatment ◽  
In Vivo Studies ◽  
Protein Activity ◽  
Oncology Research ◽  
Wide Range

e15594 Background: Protein kinase CSNK2 (CK2) is a pleiotropic serine/threonine kinase whose expression levels are frequently elevated in solid and hematologic malignancies. CSNK2 has been discovered to hold prognostic and therapeutic significance across multiple cancers and is an excellent target for oncology research. This systematic review summarizes the current knowledge from in vitro and in vivo studies on the biology of this kinase in cancer alongside pre-clinical/clinical investigations from 24 different human cancer types. Methods: PRISMA methodology was used to generate a study protocol and building-block search strategy, from which a total of 796 publications in PubMed were retrieved across 24 human cancers. 245 of these publications met both screening and inclusion criteria. Data was then systematically extracted, including information about CSNK2 subunit mRNA/protein/activity levels, phosphorylation targets, phenotypic changes, in vivo studies, and prognostic/therapeutic data. The data was thereafter summarized and analyzed. Results: Five targets phosphorylated by CSNK2 were identified in at least 4 cancers: AKT, STAT3, RELA, PTEN, and TP53. The most heavily cited was AKT, identified in 15 cancers. Phenotypically, behaviors influenced by CSNK2 that were reported in 11 or more cancers included: evasion of apoptosis, enhancement of proliferation, enhancement of invasion/metastasis, and cell cycle control. Interestingly, these pathways correlated heavily with the most commonly cited CSNK2 targets. From a clinical perspective, CSNK2 held prognostic significance in 17 of the cancers. Additionally, xenograft experiments were found to have been performed in 13 cancers where CSNK2 inhibition resulted in a positive response to treatment. Lastly, early studies have shown promising results through the clinical application of CSNK2-specific inhibitors, with several clinical trials now underway for further assessment. Conclusions: Overall, our analysis supports CSNK2 as an attractive target for cancer therapy and points to specific areas where additional investigation is critical to advance our understanding of CSNK2 biology. The design of targeted therapies by exploiting the pathophysiology of CSNK2 has the potential to generate impactful treatment strategies across a wide range of cancers, promising exciting new discoveries scientifically and clinically.

scholarly journals USE OF MICRONUCLEUS EXPERIMENTS FOR THE DETECTION OF HUMAN CANCER RISKS: A BRIEF OVERVIEW

2021 ◽  
Vol 65 (2) ◽  
Author(s):  
Armen Nersesyan ◽  
◽  
Miroslav Mišík ◽  
Andriy Cherkas ◽  
Viktoria Serhiyenko ◽  
...  
Keyword(s):  
Blood Cells ◽  
Environmental Control ◽  
Human Cancer ◽  
Occupational Exposures ◽  
Human Biomonitoring ◽  
Target Cells ◽  
Cancer Risks ◽  
Wide Range

Introduction. Micronuclei (MN) are small extranuclear DNA-containing structures that are formed as a consequence of structural and numerical chromosomal aberrations. The advantage of MN experiments compared to conventional chromosomal analyses in metaphase cells is that the scoring is by far less time consuming and laborious. MN experiments are currently widely used for the routine screening of chemicals in vitro and in vivo but also for environmental control and human biomonitoring Objectives. The purpose of this review was to collect data on the use of MN experiments for the detection of increased cancer risks as a consequence of environmental, lifestyle and occupational exposures and the detection/diagnosis of different forms of cancer. Methods. Analysis of the literature on methods for MN experiments with humans; as well as the use of this technique in different areas of research. Results. To date, a wide range of protocols for human biomonitoring studies has been developed for the measurement of MN formation in peripheral blood cells and in epithelial from different organs (buccal and nasal cavity, cervix and bladder). In addition to MN, other nuclear anomalies can be scored which reflect genetic instability as well as acute toxicity and the division of target cells. Conclusions. The evidence is accumulating that MN can be used as a diagnostic tool for the detection of increased cancer risks as well as for the early diagnosis of cervical and bladder cancer

Interferons in the treatment of human cancer.

1984 ◽  
Vol 2 (4) ◽  
pp. 336-352 ◽  
Author(s):  
J M Kirkwood ◽  
M S Ernstoff
Keyword(s):  
Recombinant Dna ◽  
Human Cancer ◽  
Clinical Results ◽  
Common Species ◽  
Current Phase ◽  
Recombinant Dna Technology ◽  
Disease States ◽  
Wide Range

The interferons are the best known of biologic antineoplastic agents. Progress with the clinical application of interferons to cancer has been slow and complicated by the need for attention to a new spectrum of therapeutic and toxic effects manifest by the interferons. This summary of current phase I and II trial results with the interferons establishes their clinical potential. The maximally tolerated dosages of the most common species of interferon alpha produced in eukaryotic cells as well as by recombinant DNA technology in bacteria are now described in a variety of different disease states. "Naturally" produced eukaryotic as well as bacterially synthesized interferons have a similar, wide range of biologic effects in vitro and in vivo. Antiviral, antiproliferative, immunologic, and enzymologic functions of the interferons relevant to antineoplastic functions are under study. Knowledge of these mechanisms should improve the clinical results obtained in human cancer. Species and subspecies differences in the activity of interferons may lead to selective use of the pure interferon subspecies, alone or in combination. The use of the interferons and other antineoplastic biologics, such as antibody or chemotherapy, are subsequent goals that are now on the horizon.

scholarly journals Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1/NF-κB–dependent DNA methyltransferase activity in acute myeloid leukemia

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2364-2373 ◽  
Author(s):  
Shujun Liu ◽  
Zhongfa Liu ◽  
Zhiliang Xie ◽  
Jiuxia Pang ◽  
Jianhua Yu ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Zinc Finger Protein ◽  
Human Cancer ◽  
Proteasomal Degradation ◽  
Physical Interaction ◽  
Dna Hypomethylation ◽  
Methyltransferase Activity ◽  
Protein Levels

Bortezomib reversibly inhibits 26S proteasomal degradation, interferes with NF-κB, and exhibits antitumor activity in human malignancies. Zinc finger protein Sp1 transactivates DNMT1 gene in mice and is functionally regulated through protein abundance, posttranslational modifications (ie, ubiquitination), or interaction with other transcription factors (ie, NF-κB). We hypothesize that inhibition of proteasomal degradation and Sp1/NF-κB–mediated transactivation may impair aberrant DNA methyltransferase activity. We show here that, in addition to inducing accumulation of polyubiquitinated proteins and abolishment of NF-κB activities, bortezomib decreases Sp1 protein levels, disrupts the physical interaction of Sp1/NF-κB, and prevents binding of the Sp1/NF-κB complex to the DNMT1 gene promoter. Abrogation of Sp1/NF-κB complex by bortezomib causes transcriptional repression of DNMT1 gene and down-regulation of DNMT1 protein, which in turn induces global DNA hypomethylation in vitro and in vivo and re-expression of epigenetically silenced genes in human cancer cells. The involvement of Sp1/NF-κB in DNMT1 regulation is further demonstrated by the observation that Sp1 knockdown using mithramycin A or shRNA decreases DNMT1 protein levels, which instead are increased by Sp1 or NF-κB overexpression. Our results unveil the Sp1/NF-κB pathway as a modulator of DNA methyltransferase activity in human cancer and identify bortezomib as a novel epigenetic-targeting drug.

scholarly journals Reduction in Surface Urokinase Receptor Forces Malignant Cells into a Protracted State of Dormancy

1997 ◽  
Vol 137 (3) ◽  
pp. 767-777 ◽  
Author(s):  
W. Yu ◽  
J. Kim ◽  
L. Ossowski
Keyword(s):  
Cancer Metastasis ◽  
Human Cancer ◽  
Metastatic Tumors ◽  
Protein Levels ◽  
Upar Expression ◽  
Full Complement ◽  
Surface Receptor ◽  
Progressive Growth

Considerable evidence links urokinase plasminogen activator (uPA) bound to its surface receptor (uPAR) with enhanced invasiveness of cancer cells. By blocking uPAR expression in human epidermoid carcinoma cells (HEp3), we have now identified an additional and novel in vivo function for this receptor by showing that receptor-deficient cells enter a state of dormancy reminiscent of that observed in human cancer metastasis. Its main characteristic is survival without signs of progressive growth. Five clones transfected with a vector expressing uPAR antisense RNA under the β-actin promoter were isolated and shown to have uPAR (at the mRNA and protein levels) reduced by 50 to 80%; four clones, transfected with vector alone and having uPAR levels similar to those of parental cells, served as controls. In confirmation of our previous results, reduced uPAR always coincided with a significantly reduced invasiveness. Each of the control clones produced rapidly growing, highly metastatic tumors within 2 wk of inoculation on chorioallantoic membranes (CAMs) of chick embryos. In contrast, each of the clones with low surface uPAR, whose proliferation rate in culture was indistinguishable from controls, remained dormant for up to 5 mo when inoculated on CAMs. Thus, the reduction in uPAR altered the phenotype of HEp3 tumor cells from tumorigenic to dormant. Although protracted, tumor dormancy was not permanent since in spite of maintaining low uPAR levels, each of the in vivo–passaged antisense clones eventually reemerged from dormancy to initiate progressive growth and to form metastases at a level of 20 to 90% of that of fully malignant control. This observation suggested that other factors, whose expression is dependent on cumulative and prolonged in vivo effects, can compensate for the lack of a full complement of surface uPAR required for the expression of malignant properties. These “reemerged,” uPAR-deficient clones were easily distinguishable from the vector-transfected controls by the fact that after only 1 wk in culture, the invasion of CAM by all five clones and tumorigenicity of four of the five clones were reduced back to the values observed before in vivo maintenance. In contrast, dissociated and in vitro–grown cells of control tumors were fully invasive and produced large, metastatic tumors when reinoculated on CAMs. Quantitation of the percent of apoptotic and S-phase cells in vivo, in the control and uPAR-deficient, dormant clones, showed that the mechanism responsible for the dormancy was a diminished proliferation.

SGN-70, a Humanized Anti-CD70 Antibody, Targets CD70-Expressing Hematologic Tumors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2492-2492
Author(s):  
Julie A. McEarchern ◽  
Charlotte F. McDonagh ◽  
Leia M. Smith ◽  
Kerry Klussman ◽  
Ezogelin Oflazoglu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Hematologic Malignancies ◽  
Myeloma Cell ◽  
Long Bone ◽  
Protein Levels ◽  
Normal Tissues ◽  
Significant Expression

Abstract Antigens expressed on malignant cells in the absence of significant expression on normal tissues are highly desirable targets for therapeutic antibodies. CD70 is a TNF superfamily member whose normal expression is restricted to activated lymphocytes but is aberrantly expressed in hematologic malignancies and solid tumors including non-Hodgkin’s lymphoma (NHL), Hodgkin’s disease, multiple myeloma (MM), Waldenstrom’s macroglobulinemia, renal cell carcinoma, glioblastoma, and nasopharyngeal carcinoma. To target CD70-expressing hematologic malignancies, we have engineered a humanized IgG1 anti-CD70 antibody that mediates lysis of tumor targets via ADCC and CDC and facilitates antibody dependent cellular phagocytosis in vitro. In vivo, administration of SGN-70 prolonged survival of SCID mice bearing CD70+ disseminated human NHL or MM xenografts. Intravenous injection of the CD70+ MM cell line MM.1S resulted in disease as measured by onset of paralysis, presence of CD138+ MM cells in the bone marrow, and increasing levels of circulating human Ig lambda light chain. SGN-70 treatment of MM.1S-bearing mice significantly delayed onset of paralysis and reduced the monoclonal protein levels detected in serum approximately 4-fold compared to untreated or non-binding antibody control-treated mice. Whereas myeloma cells comprised 32±6.4 % of mononuclear cells in the long bone marrow of control mice, SGN-70 treatment reduced the myeloma cell fraction to 4.9±1.9% of mononuclear cells recovered. SGN-70 treatment also significantly extended the survival of mice bearing disseminated Raji tumors (NHL) compared to control mice. Survival benefit was absent when mice received an Fc-modified antibody deficient in effector functions, confirming that the activity of SGN-70 in these models was dependent upon Fc-FcγR interaction with host immune cells. Together, these data demonstrate that SGN-70 possesses effector cell-mediated antitumor activity and provides rationale for clinical study of SGN-70 in CD70+ hematologic malignancies.

scholarly journals Engineered exosomes delivering specific tumor-suppressive RNAi attenuate oral cancer progression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yutaro Kase ◽  
Katsuhiro Uzawa ◽  
Sho Wagai ◽  
Shusaku Yoshimura ◽  
Jun-Ichiro Yamamoto ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Cancer Progression ◽  
Human Cancer ◽  
Suppressive Effect ◽  
Human Cancer Cells ◽  
Barr Virus ◽  
Wide Range ◽  
Oncogenic Activity

AbstractExosomes are involved in a wide range of biological processes in human cells. Considerable evidence suggests that engineered exosomes (eExosomes) containing therapeutic agents can attenuate the oncogenic activity of human cancer cells. Despite its biomedical relevance, no information has been available for oral squamous cell carcinoma (OSCC), and therefore the development of specific OSCC-targeting eExosomes (octExosomes) is urgently needed. We demonstrated that exosomes from normal fibroblasts transfected with Epstein–Barr Virus Induced-3 (EBI3) cDNA were electroporated with siRNA of lymphocyte cytoplasmic protein 1 (LCP1), as octExosomes, and a series of experiments were performed to evaluate the loading specificity/effectiveness and their anti-oral cancer cell activities after administration of octExosomes. These experiments revealed that octExosomes were stable, effective for transferring siLCP1 into OSCC cells and LCP1 was downregulated in OSCC cells with octExosomes as compared with their counterparts, leading to a significant tumor-suppressive effect in vitro and in vivo. Here we report the development of a new valuable tool for inhibiting tumor cells. By engineering exosomes, siLCP1 was transferred to specifically suppress oncogenic activity of OSCC cells. Inhibition of other types of human malignant cells merits further study.

scholarly journals YBX1 mediates translation of oncogenic transcripts to control cell competition in AML

Leukemia ◽  
2021 ◽  
Author(s):  
Florian Perner ◽  
Tina M. Schnoeder ◽  
Yijun Xiong ◽  
Ashok Kumar Jayavelu ◽  
Nomusa Mashamba ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Control Cell ◽  
Hematologic Malignancies ◽  
Malignant Cells ◽  
Cell Competition ◽  
Normal Cells ◽  
Protein Levels ◽  
Oncogenic Protein

AbstractPersistence of malignant clones is a major determinant of adverse outcome in patients with hematologic malignancies. Despite the fact that the majority of patients with acute myeloid leukemia (AML) achieve complete remission after chemotherapy, a large proportion of them relapse as a result of residual malignant cells. These persistent clones have a competitive advantage and can re-establish disease. Therefore, targeting strategies that specifically diminish cell competition of malignant cells while leaving normal cells unaffected are clearly warranted. Recently, our group identified YBX1 as a mediator of disease persistence in JAK2-mutated myeloproliferative neoplasms. The role of YBX1 in AML, however, remained so far elusive. Here, inactivation of YBX1 confirms its role as an essential driver of leukemia development and maintenance. We identify its ability to amplify the translation of oncogenic transcripts, including MYC, by recruitment to polysomal chains. Genetic inactivation of YBX1 disrupts this regulatory circuit and displaces oncogenic drivers from polysomes, with subsequent depletion of protein levels. As a consequence, leukemia cells show reduced proliferation and are out-competed in vitro and in vivo, while normal cells remain largely unaffected. Collectively, these data establish YBX1 as a specific dependency and therapeutic target in AML that is essential for oncogenic protein expression.

scholarly journals Effect of a Drug Delivery System Made of Quercetin Formulated into PEGylation Liposomes on Cervical Carcinoma In Vitro and In Vivo

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Jian Li ◽  
Zhen Li ◽  
Yanting Gao ◽  
Shihe Liu ◽  
Kun Li ◽  
...  
Keyword(s):  
Cervical Carcinoma ◽  
Slow Release ◽  
Malignant Tumors ◽  
Human Cancer ◽  
Drug Loading ◽  
Human Cancer Cell Lines ◽  
Solubility Improvement ◽  
Wide Range

Quercetin is a well-known flavonoid for its potent antitumor and antiproliferative effects on a wide range of human cancer cell lines. However, the delivery of quercetin is challenging due to its extreme insolubility in water. The intention of this study was to evaluate the antitumor effect of quercetin-loaded PEGylated liposomes (PEG-Que-NLs) in vitro and in vivo. We first prepared PEG-Que-NLs by method of thin film hydration; further determined, the optimum ratios of quercetin to Soybean phosphatidylcholine (SPC), to cholesterol (CHL), and to PEG-4000 were 1 : 8, 1 : 2, and 1 : 2 ( w / w ), respectively, and the optimal hydration temperature was 55°C when the mean vesicle diameter and apparent Zeta potential of PEG-Que-NLs were found to be 171.3 ± 10.4  nm and − 13.1 ± 2.1  mV, respectively; the encapsulation efficiency and the drug loading of PEG-Que-NLs were 81.25 ± 3.12 % and 8.5 ± 0.77 % , respectively. Drug release study in vitro showed that PEG-Que-NLs exhibited a slow-release effect without significant burst effect. Furthermore, the inhibition effect of PEG-Que-NLs on HeLa cells was considerably higher than free quercetin (free-Que) and quercetin liposomes (Que-NLs). Intravenous injection of PEG-Que-NLs into U14 bearing mouse models inhibited the cervical carcinoma growth significantly, and the tumor inhibition rate was much higher than free-Que and Que-NLs. These results of this study indicated that PEG-Que-NLs exhibited potential application prospects in the treatment of malignant tumors because of its tumor targeting, slow-release properties, and the solubility improvement of quercetin.

Evaluation of 99mTc-Label led Vitamin K4 as an Agent for Testicular Imaging

1991 ◽  
Vol 30 (01) ◽  
pp. 35-39 ◽  
Author(s):  
H. S. Durak ◽  
M. Kitapgi ◽  
B. E. Caner ◽  
R. Senekowitsch ◽  
M. T. Ercan
Keyword(s):  
Soft Tissue ◽  
Room Temperature ◽  
Normal Subjects ◽  
Left Testis ◽  
Wide Range ◽  
Activity Ratios ◽  
The Right ◽  
Radioactivity Levels

Vitamin K4 was labelled with 99mTc with an efficiency higher than 97%. The compound was stable up to 24 h at room temperature, and its biodistribution in NMRI mice indicated its in vivo stability. Blood radioactivity levels were high over a wide range. 10% of the injected activity remained in blood after 24 h. Excretion was mostly via kidneys. Only the liver and kidneys concentrated appreciable amounts of radioactivity. Testis/soft tissue ratios were 1.4 and 1.57 at 6 and 24 h, respectively. Testis/blood ratios were lower than 1. In vitro studies with mouse blood indicated that 33.9 ±9.6% of the radioactivity was associated with RBCs; it was washed out almost completely with saline. Protein binding was 28.7 ±6.3% as determined by TCA precipitation. Blood clearance of 99mTc-l<4 in normal subjects showed a slow decrease of radioactivity, reaching a plateau after 16 h at 20% of the injected activity. In scintigraphic images in men the testes could be well visualized. The right/left testis ratio was 1.08 ±0.13. Testis/soft tissue and testis/blood activity ratios were highest at 3 h. These ratios were higher than those obtained with pertechnetate at 20 min post injection.99mTc-l<4 appears to be a promising radiopharmaceutical for the scintigraphic visualization of testes.

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