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Folahan JT, Barabutis N. NEK kinases in cell cycle regulation, DNA damage response, and cancer progression. Tissue Cell 2025; 94:102811. [PMID: 40037068 PMCID: PMC11912005 DOI: 10.1016/j.tice.2025.102811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 02/16/2025] [Accepted: 02/21/2025] [Indexed: 03/06/2025]
Abstract
The NIMA-related kinase (NEK) family of serine/threonine kinases is essential for the regulation of cell cycle progression, mitotic spindle assembly, and genomic stability. In this review, we explore the structural and functional diversity of NEK kinases, highlighting their roles in both canonical and non-canonical cellular processes. We examine recent preclinical findings on NEK inhibition, showcasing promising results for NEK-targeted therapies, particularly in cancer types characterized by high NEK expression. We discussed the therapeutic potential of targeting NEKs as modulators of cell cycle and DDR pathways, with a focus on identifying strategies to exploit NEK activity for enhanced treatment efficacy. Future research directions are proposed to further elucidate NEK-mediated mechanisms and to develop selective inhibitors that target NEK-related pathways.
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Affiliation(s)
- Joy T Folahan
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA 71201, USA
| | - Nektarios Barabutis
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA 71201, USA.
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2
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Ruß AK, Schreiber S, Lieb W, Vehreschild JJ, Heuschmann PU, Illig T, Appel KS, Vehreschild MJGT, Krefting D, Reinke L, Viebke A, Poick S, Störk S, Reese JP, Zoller T, Krist L, Ellinghaus D, Foesel BU, Gieger C, Lorenz-Depiereux B, Witzenrath M, Anton G, Krawczak M, Heyckendorf J, Bahmer T. Genome-wide association study of post COVID-19 syndrome in a population-based cohort in Germany. Sci Rep 2025; 15:15791. [PMID: 40328884 PMCID: PMC12056214 DOI: 10.1038/s41598-025-00945-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 05/02/2025] [Indexed: 05/08/2025] Open
Abstract
If health impairments due to coronavirus disease 2019 (COVID-19) persist for 12 weeks or longer, patients are diagnosed with Post-COVID Syndrome (PCS), or Long-COVID. Although the COVID-19 pandemic has largely subsided in 2024, PCS is still a major health burden worldwide, and identifying potential genetic modifiers of PCS remains of great clinical and scientific interest. We therefore performed a case-control type genome-wide association study (GWAS) of three recently developed PCS (severity) scores in 2,247 participants of COVIDOM, a prospective, multi-centre, population-based cohort study of SARS-CoV-2-infected individuals in Germany. Each PCS score originally represented the weighted sum of the binary indicators of all, or a subset, of 12 PCS symptom complexes, assessed six months or later after the PCR test-confirmed SARS-CoV-2 infection of a participant. For various methodical reasons, however, the PCS scores were dichotomized along their respective median values in the present study, prior to the GWAS. Of the 6,383,167 single nucleotide polymorphisms included, various variants were found to be associated with at least one of the PCS scores, although not at the stringent genome-wide statistical significance level of 5 × 10- 8. With p = 6.6 × 10- 8, however, the genotype-phenotype association of SNP rs9792535 at position chr9:127,166,653 narrowly missed this threshold. The SNP is located in a region including the NEK6, PSMB7 and ADGRD2 genes which, however, does not immediately suggest an etiological connection to PCS. As regards functional plausibility, variants of a possible effect mapped to the olfactory receptor gene region (lead SNP rs10893121 at position chr11:123,854,744; p = 2.5 × 10- 6). Impairment of smell and taste is a pathognomonic feature of both, acute COVID-19 and PCS, and our results suggest that this connection may have a genetic basis. Three other genotype-phenotype associations pointed towards a possible etiological role in PCS of cellular virus repression (CHD6 gene region), activation of macrophages (SLC7A2) and the release of virus particles from infected cells (ARHGAP44). All other gene regions highlighted by our GWAS did not relate to pathophysiological processes currently discussed for PCS. Therefore, and because the genotype-phenotype associations observed in our GWAS were generally not very strong, the complexity of the genetic background of PCS appears to be as high as that of most other multifactorial traits in humans.
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Affiliation(s)
- Anne-Kathrin Ruß
- Institute of Medical Informatics and Statistics, University Medical Center Schleswig-Holstein, Kiel University, Brunswiker Straße 10, 24113, Kiel, Germany
- Institute of Epidemiology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany
| | - Stefan Schreiber
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Wolfgang Lieb
- Institute of Epidemiology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany
| | - J Janne Vehreschild
- Institute of Digital Medicine and Clinical Data Science, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany
- Department I of Internal Medicine, Faculty of Medicine, University Hospital CologneUniversity of Cologne, Cologne, Germany
| | - Peter U Heuschmann
- Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany
- Institute of Medical Data Science, University Hospital Würzburg, Würzburg, Germany
- Clinical Trial Center, University Hospital Würzburg, Würzburg, Germany
| | - Thomas Illig
- Hannover Unified Biobank, Hannover Medical School, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
| | - Katharina S Appel
- Institute of Digital Medicine and Clinical Data Science, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany
| | - Maria J G T Vehreschild
- Medical Department 2, Center for Internal Medicine, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany
| | - Dagmar Krefting
- Department of Medical Informatics, University Medical Center Göttingen, Göttingen, Germany
- Campus Institute Data Sciences, Göttingen, Germany
| | - Lennart Reinke
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Alin Viebke
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Susanne Poick
- Institute of Epidemiology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Stefan Störk
- Department of Clinical Research and Epidemiology, Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany
- Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
| | - Jens-Peter Reese
- Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany
- Institute of Medical Data Science, University Hospital Würzburg, Würzburg, Germany
- Faculty of Health Sciences, THM University of Applied Sciences, Gießen, Germany
| | - Thomas Zoller
- Department of Infectious Diseases, Respiratory and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Lilian Krist
- Institute of Social Medicine, Epidemiology and Health Economics, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - David Ellinghaus
- Institute of Clinical Molecular Biology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany
| | - Bärbel U Foesel
- Institute of Epidemiology, Research Unit of Molecular Epidemiology, Helmholtz Munich - German Research Center for Environmental Health, Neuherberg, Germany
| | - Christian Gieger
- Institute of Epidemiology, Research Unit of Molecular Epidemiology, Helmholtz Munich - German Research Center for Environmental Health, Neuherberg, Germany
| | - Bettina Lorenz-Depiereux
- Institute of Epidemiology, Research Unit of Molecular Epidemiology, Helmholtz Munich - German Research Center for Environmental Health, Neuherberg, Germany
| | - Martin Witzenrath
- Department of Infectious Diseases and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
- CAPNETZ Stiftung, Hannover, Germany
| | - Gabriele Anton
- Medical School OWL, Bielefeld University, Bielefeld, Germany
| | - Michael Krawczak
- Institute of Medical Informatics and Statistics, University Medical Center Schleswig-Holstein, Kiel University, Brunswiker Straße 10, 24113, Kiel, Germany.
| | - Jan Heyckendorf
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
- Airway Research Center North (ARCN), German Center for Lung Research (DZL), Großhansdorf, Germany
- Leibniz Lung Clinic, Kiel, Germany
| | - Thomas Bahmer
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
- Airway Research Center North (ARCN), German Center for Lung Research (DZL), Großhansdorf, Germany
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Panchal NK, Mohanty S, Prince SE. Computational insights into NIMA-related kinase 6: unraveling mutational effects on structure and function. Mol Cell Biochem 2024; 479:2989-3009. [PMID: 38117419 DOI: 10.1007/s11010-023-04910-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 11/25/2023] [Indexed: 12/21/2023]
Abstract
The NEK6 (NIMA-related kinase 6) serine/threonine kinase is a pivotal player in a multitude of cellular processes, including the regulation of the cell cycle and the response to DNA damage. Its significance extends to disease pathogenesis, as changes in NEK6 activity have been linked to the development of cancer. Non-synonymous single nucleotide polymorphisms (nsSNPs) in NEK6 have been linked to cancer as they alter the protein's native structure and function. The association between NEK6 activity and cancer development has prompted researchers to explore the effects of genetic variations within the NEK6 gene. Therefore, we utilized advanced computational tools to analyze 155 high-confidence nsSNPs in the NEK6 gene. From this analysis, 21 nsSNPs were identified as potentially harmful, raising concerns about their impact on NEK6 activity and cancer risk. These 21 mutations were then examined for structural alterations, and eight of nsSNPs (I51M, V76A, I134N, Y152D, R171Q, V186G, L237R, and C285S) were found to destabilize the protein. Among the destabilizing mutations screened, a specific mutation, R171Q, stood out due to its conserved nature. To understand its impact on the protein and conformation, all-atom molecular dynamics simulations (MDS) for 100 ns were performed for both Wildtype NEK6 (WT-NEK6) and R171Q. The simulations revealed that the R171Q variant was unstable and led to significant conformational changes in NEK6. This study provides valuable insights into NEK6 dysfunction caused by single amino acid alterations, offering a novel understanding of the molecular mechanisms underlying NEK6-related cancer progression.
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Affiliation(s)
- Nagesh Kishan Panchal
- Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632 014, India
| | - Shruti Mohanty
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, India
| | - Sabina Evan Prince
- Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632 014, India.
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Zhang Y, Guo W, Zhan Z, Bai O. Carcinogenic mechanisms of virus-associated lymphoma. Front Immunol 2024; 15:1361009. [PMID: 38482011 PMCID: PMC10932979 DOI: 10.3389/fimmu.2024.1361009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 02/12/2024] [Indexed: 04/17/2024] Open
Abstract
The development of lymphoma is a complex multistep process that integrates numerous experimental findings and clinical data that have not yet yielded a definitive explanation. Studies of oncogenic viruses can help to deepen insight into the pathogenesis of lymphoma, and identifying associations between lymphoma and viruses that are established and unidentified should lead to cellular and pharmacologically targeted antiviral strategies for treating malignant lymphoma. This review focuses on the pathogenesis of lymphomas associated with hepatitis B and C, Epstein-Barr, and human immunodeficiency viruses as well as Kaposi sarcoma-associated herpesvirus to clarify the current status of basic information and recent advances in the development of virus-associated lymphomas.
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Affiliation(s)
| | | | | | - Ou Bai
- Department of Hematology, The First Hospital of Jilin University, Changchun, Jilin, China
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Wu X, Deng K, Cai H, Zeng Z, Cao J, Zhang L, Lu Z, Cheng W. Nek6 knockdown polarized macrophages into a pro-inflammatory phenotype via inhibiting STAT3 expression. Int J Exp Pathol 2023; 104:237-246. [PMID: 37431082 PMCID: PMC10500168 DOI: 10.1111/iep.12489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 05/08/2023] [Accepted: 06/18/2023] [Indexed: 07/12/2023] Open
Abstract
Recently macrophage polarization has emerged as playing an essential role in the oathogenesis of atherosclerosis, which is the most important underlying process in many types of cardiovascular diseases. Although Nek6 has been reported to be involved in various cellular processes, the effect of Nek6 on macrophage polarization remains unknown. Macrophages exposed to lipopolysaccharide (LPS) or IL-4 were used to establish an in vitro model for the study of regulation of classically (M1) or alternatively (M2) activated macrophage. Bone marrow-derived macrophages (BMDMs) transfected with short hairpin RNA-targeting Nek6 were then in functional studies. We observed that Nek6 expression was decreased in both peritoneal macrophages (PMs) and BMDMs stimulated by LPS. This effect was seen at both mRNA and protein level. The opposite results were obtained after administration of IL-4. Macrophage-specific Nek6 knockdown significantly exacerbated pro-inflammatory M1 polarized macrophage gene expression in response to LPS challenge, but the anti-inflammatory response gene expression that is related to M2 macrophages was attenuated by Nek6 silencing followed by treatment with IL-4. Mechanistic studies exhibited that Nek6 knockdown inhibited the phosphorylated STAT3 expression that mediated the effect on macrophage polarization regulated by AdshNek6. Moreover, decreased Nek6 expression was also observed in atherosclerotic plaques. Collectively, these evidences suggested that Nek6 acts as a crucial site in macrophage polarization, and that this operates in a STAT3-dependent manner.
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Affiliation(s)
- Xiaoyan Wu
- Department of Cardiology, Zhongnan HospitalWuhan UniversityWuhanChina
- Institute of Myocardial Injury and RepairWuhan UniversityWuhanChina
| | - Ke‐Qiong Deng
- Department of Cardiology, Zhongnan HospitalWuhan UniversityWuhanChina
- Institute of Myocardial Injury and RepairWuhan UniversityWuhanChina
| | - Huan‐Huan Cai
- Department of Cardiology, Zhongnan HospitalWuhan UniversityWuhanChina
- Institute of Myocardial Injury and RepairWuhan UniversityWuhanChina
| | - Ziyue Zeng
- Department of Cardiology, Zhongnan HospitalWuhan UniversityWuhanChina
- Institute of Myocardial Injury and RepairWuhan UniversityWuhanChina
| | - Jian‐Lei Cao
- Department of Cardiology, Zhongnan HospitalWuhan UniversityWuhanChina
- Institute of Myocardial Injury and RepairWuhan UniversityWuhanChina
| | - Lin Zhang
- Department of Cardiology, Zhongnan HospitalWuhan UniversityWuhanChina
- Institute of Myocardial Injury and RepairWuhan UniversityWuhanChina
| | - Zhibing Lu
- Department of Cardiology, Zhongnan HospitalWuhan UniversityWuhanChina
- Institute of Myocardial Injury and RepairWuhan UniversityWuhanChina
| | - Wen‐Lin Cheng
- Department of Cardiology, Zhongnan HospitalWuhan UniversityWuhanChina
- Institute of Myocardial Injury and RepairWuhan UniversityWuhanChina
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Zhang H, Li B. NIMA-related kinase 6 as an effective target inhibits the hepatocarcinogenesis and progression of hepatocellular carcinoma. Heliyon 2023; 9:e15971. [PMID: 37260886 PMCID: PMC10227323 DOI: 10.1016/j.heliyon.2023.e15971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 04/26/2023] [Accepted: 04/27/2023] [Indexed: 06/02/2023] Open
Abstract
Background NIMA-related kinase 6 (NEK 6) is over-expressed in some tumor cell lines and tissues. However, its expression in hepatocellular carcinoma (HCC) and its correlation with clinical features remain unclear. Methods Total RNA from HCC liver tissues, other liver specimens, and hepatic cell lines was extracted and QPCR was adopted to detect NEK6 expression. The correlation between NEK6 expression and the clinical characteristics of HCC was analyzed. Scratch assay, Transwell assay, and tumor-formation assay were used to evaluate the effects of NEK6 on the HCC progression in vitro and in vivo. Results The expression of NEK6 was up-regulated in HCC tissues and HCC cell lines: Li-7 and HepG2. The overexpression of NEK6 was correlated with hepatitis B virus infection and tumor diameter (P = 0.045). When down-regulated the expression of NEK6, both the migration and invasion capabilities of Li-7 and HepG2 cells and the growth of xenograft tumors were suppressed. (P < 0.05). Conclusions NEK6 expression was up-regulated in HCC and correlated with the progression, suggesting it might be a valuable biomarker and a potential therapeutic target for HCC.
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Affiliation(s)
- Hao Zhang
- Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Bo Li
- Department of Hepatobiliary Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
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Shao S, Xiao L, Jia M, Zhang C, Zhao G, Yao R, Wang X, Gao L. Never in mitosis gene A-related kinase-6 deficiency deteriorates diabetic cardiomyopathy via regulating heat shock protein 72. J Mol Med (Berl) 2023; 101:419-430. [PMID: 36867206 DOI: 10.1007/s00109-023-02295-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 02/01/2023] [Accepted: 02/06/2023] [Indexed: 03/04/2023]
Abstract
NIMA (never in mitosis, gene A)-related kinase-6 (NEK6), a cell cycle regulatory gene, was found to regulate cardiac hypertrophy. However, its role in diabetes-induced cardiomyopathy has not been fully elucidated. This research was designed to illustrate the effect of NEK6 involved in diabetic cardiomyopathy. Here we used a streptozotocin (STZ)-induced mice diabetic cardiomyopathy model and NEK6 knockout mice to explore the role and mechanism of NEK6 in diabetic-induced cardiomyopathy. NEK6 knockout mice and wild-type littermates were subjected to STZ injection (50 mg/kg/day for 5 days) to induce a diabetic cardiomyopathy model. As a result, 4 months after final STZ injection, DCM mice revealed cardiac hypertrophy, fibrosis, and systolic and diastolic dysfunction. NEK6 deficiency causes deteriorated cardiac hypertrophy, fibrosis, and cardiac dysfunction. Furthermore, we observed inflammation and oxidative stress in the hearts of NEK6 deficiency mice under diabetic cardiomyopathy pathology. Adenovirus was used to upregulate NEK6 in neonatal rat cardiomyocytes, and it was found that NEK6 ameliorated high glucose-induced inflammation and oxidative stress. Our findings revealed that NEK6 increased the phosphorylation of heat shock protein 72 (HSP72) and increased the protein level of PGC-1α and NRF2. Co-IP assay experiment confirmed that NEK6 interacted with HSP72. When HSP72 was silenced, the anti-inflammation and anti-oxidative stress effects of NEK6 were blurred. In summary, NEK6 may protect diabetic-induced cardiomyopathy by interacting with HSP72 and promoting the HSP72/PGC-1α/NRF2 signaling. KEY MESSAGES: NEK6 knockout deteriorated cardiac dysfunction, cardiac hypertrophy, fibrosis as well as inflammation response, and oxidative stress. NEK6 overexpression attenuated high glucose induced inflammation and oxidative stress. The underlying mechanisms of the protective role of NEK6 in the development of diabetic cardiomyopathy seem to involve the regulation of HSP72-NRF2- PGC-1α pathway. NEK6 may become a new therapeutic target for diabetic cardiomyopathy.
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Affiliation(s)
- Shuangyin Shao
- Department of Cardiovascular Surgery, Henan Provincial Chest Hospital, Zhengzhou University, Zhengzhou, 450000, China
| | - Lili Xiao
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, China
| | - Meng Jia
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chuyang Zhang
- Department of Education, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guojun Zhao
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, China
| | - Rui Yao
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, China
| | - Xiaofang Wang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, China.
| | - Lu Gao
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, China.
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Panchal NK, Mohanty S, Prince SE. NIMA-related kinase-6 (NEK6) as an executable target in cancer. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2023; 25:66-77. [PMID: 36074296 DOI: 10.1007/s12094-022-02926-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 08/09/2022] [Indexed: 01/07/2023]
Abstract
Cancer is a disease that develops when cells begin to divide uncontrollably and spreads to other parts of the body. Proliferation and invasion of cancerous cells are generally known to be influenced by cell cycle-related proteins in human malignancies. Therefore, in this review, we have emphasized on the serine/threonine kinase named NEK6. NEK6 is been deliberated to play a critical role in mitosis progression that includes mitotic spindle formation, metaphase to anaphase transition, and centrosome separation. Moreover, it has a mechanistic role in DNA repair and can cause apoptosis when inhibited. Past studies have connected NEK6 protein expression to cancer cell senescence. Besides, there are reports relating NEK6 to a range of malignancies including breast, lung, ovarian, prostate, kidney, liver, and others. Given its significance, this review attempts to describe the structural and functional aspects of NEK6 in various cellular processes, as well as how it is linked to different forms of cancer. Lastly, we have accentuated, on some of the plausible inhibitors that have been explored against NEK6 overexpression.
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Affiliation(s)
- Nagesh Kishan Panchal
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, India
| | - Shruti Mohanty
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, India
| | - Sabina Evan Prince
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, India.
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Joseph BB, Edeen PT, Meadows S, Binti S, Fay DS. An unexpected role for the conserved ADAM-family metalloprotease ADM-2 in Caenorhabditis elegans molting. PLoS Genet 2022; 18:e1010249. [PMID: 35639786 PMCID: PMC9187072 DOI: 10.1371/journal.pgen.1010249] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 06/10/2022] [Accepted: 05/11/2022] [Indexed: 11/18/2022] Open
Abstract
Molting is a widespread developmental process in which the external extracellular matrix (ECM), the cuticle, is remodeled to allow for organismal growth and environmental adaptation. Studies in the nematode Caenorhabditis elegans have identified a diverse set of molting-associated factors including signaling molecules, intracellular trafficking regulators, ECM components, and ECM-modifying enzymes such as matrix metalloproteases. C. elegans NEKL-2 and NEKL-3, two conserved members of the NEK family of protein kinases, are essential for molting and promote the endocytosis of environmental steroid-hormone precursors by the epidermis. Steroids in turn drive the cyclic induction of many genes required for molting. Here we report a role for the sole C. elegans ADAM–meltrin metalloprotease family member, ADM-2, as a mediator of molting. Loss of adm-2, including mutations that disrupt the metalloprotease domain, led to the strong suppression of molting defects in partial loss-of-function nekl mutants. ADM-2 is expressed in the epidermis, and its trafficking through the endo-lysosomal network was disrupted after NEKL depletion. We identified the epidermally expressed low-density lipoprotein receptor–related protein, LRP-1, as a candidate target of ADM-2 regulation. Whereas loss of ADM-2 activity led to the upregulation of apical epidermal LRP-1, ADM-2 overexpression caused a reduction in LRP-1 levels. Consistent with this, several mammalian ADAMs, including the meltrin ADAM12, have been shown to regulate mammalian LRP1 via proteolysis. In contrast to mammalian homologs, however, the regulation of LRP-1 by ADM-2 does not appear to involve the metalloprotease function of ADM-2, nor is proteolytic processing of LRP-1 strongly affected in adm-2 mutants. Our findings suggest a noncanonical role for an ADAM family member in the regulation of a lipoprotein-like receptor and lead us to propose that endocytic trafficking may be important for both the internalization of factors that promote molting as well as the removal of proteins that can inhibit the process. The molecular and cellular features of molting in nematodes share many similarities with cellular and developmental processes that occur in mammals. This includes the degradation and reorganization of extracellular matrix materials that surround cells, as well as the intracellular machineries that allow cells to sample and modify their environments. In the current study, we found an unexpected function for a conserved protein that cleaves other proteins on the external surface of cells. Rather than promoting molting through extracellular matrix reorganization, however, the ADM-2 protease appears to function as a negative regulator of molting. This observation can be explained in part by data showing that ADM-2 negatively regulates a cell surface receptor required for molting. Surprisingly, it appears to do so through a mechanism that does not involve proteolysis. Our data provide insights into the mechanisms controlling molting and link several conserved proteins to show how they function together during development.
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Affiliation(s)
- Braveen B. Joseph
- Department of Molecular Biology, College of Agriculture and Natural Resources, University of Wyoming, Laramie, Wyoming, United States of America
| | - Phillip T. Edeen
- Department of Molecular Biology, College of Agriculture and Natural Resources, University of Wyoming, Laramie, Wyoming, United States of America
| | - Sarina Meadows
- Department of Molecular Biology, College of Agriculture and Natural Resources, University of Wyoming, Laramie, Wyoming, United States of America
| | - Shaonil Binti
- Department of Molecular Biology, College of Agriculture and Natural Resources, University of Wyoming, Laramie, Wyoming, United States of America
| | - David S. Fay
- Department of Molecular Biology, College of Agriculture and Natural Resources, University of Wyoming, Laramie, Wyoming, United States of America
- * E-mail:
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In Mitosis You Are Not: The NIMA Family of Kinases in Aspergillus, Yeast, and Mammals. Int J Mol Sci 2022; 23:ijms23074041. [PMID: 35409400 PMCID: PMC8999480 DOI: 10.3390/ijms23074041] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 11/17/2022] Open
Abstract
The Never in mitosis gene A (NIMA) family of serine/threonine kinases is a diverse group of protein kinases implicated in a wide variety of cellular processes, including cilia regulation, microtubule dynamics, mitotic processes, cell growth, and DNA damage response. The founding member of this family was initially identified in Aspergillus and was found to play important roles in mitosis and cell division. The yeast family has one member each, Fin1p in fission yeast and Kin3p in budding yeast, also with functions in mitotic processes, but, overall, these are poorly studied kinases. The mammalian family, the main focus of this review, consists of 11 members named Nek1 to Nek11. With the exception of a few members, the functions of the mammalian Neks are poorly understood but appear to be quite diverse. Like the prototypical NIMA, many members appear to play important roles in mitosis and meiosis, but their functions in the cell go well beyond these well-established activities. In this review, we explore the roles of fungal and mammalian NIMA kinases and highlight the most recent findings in the field.
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Yang M, Guo Y, Guo X, Mao Y, Zhu S, Wang N, Lu D. Analysis of the effect of NEKs on the prognosis of patients with non-small-cell lung carcinoma based on bioinformatics. Sci Rep 2022; 12:1705. [PMID: 35105934 PMCID: PMC8807624 DOI: 10.1038/s41598-022-05728-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 01/14/2022] [Indexed: 12/14/2022] Open
Abstract
NEKs are proteins that are involved in various cell processes and play important roles in the formation and development of cancer. However, few studies have examined the role of NEKs in the development of non-small-cell lung carcinoma (NSCLC). To address this problem, the Oncomine, UALCAN, and the Human Protein Atlas databases were used to analyze differential NEK expression and its clinicopathological parameters, while the Kaplan-Meier, cBioPortal, GEPIA, and DAVID databases were used to analyze survival, gene mutations, similar genes, and biological enrichments. The rate of NEK family gene mutation was high (> 50%) in patients with NSCLC, in which NEK2/4/6/8/ was overexpressed and significantly correlated with tumor stage and nodal metastasis status. In addition, the high expression of NEK2/3mRNA was significantly associated with poor prognosis in patients with NSCLC, while high expression of NEK1/4/6/7/8/9/10/11mRNA was associated with good prognosis. In summary, these results suggest that NEK2/4/6/8 may be a potential prognostic biomarker for the survival of patients with NSCLC.
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Affiliation(s)
- Mengxia Yang
- Graduate School, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China.,Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, People's Republic of China
| | - Yikun Guo
- Graduate School, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China
| | - Xiaofei Guo
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, People's Republic of China
| | - Yun Mao
- Department of Oncology, The Second Hospital of Hunan University of Chinese Medicine, Changsha, 410005, People's Republic of China
| | - Shijie Zhu
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, People's Republic of China
| | - Ningjun Wang
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, People's Republic of China.
| | - Dianrong Lu
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, People's Republic of China.
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Yu Y, Shen T, Zhong X, Wang LL, Tai W, Zou Y, Qin J, Zhang Z, Zhang CL. NEK6 is an injury-responsive kinase cooperating with STAT3 in regulation of reactive astrogliosis. Glia 2021; 70:273-286. [PMID: 34643969 DOI: 10.1002/glia.24104] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 11/08/2022]
Abstract
In response to brain injury, resident astrocytes become reactive and play dynamic roles in neural repair and regeneration. The signaling pathways underlying such reactive astrogliosis remain largely unclear. We here show that NEK6, a NIMA-related serine/threonine protein kinase, is rapidly induced following pathological stimulations and plays critical roles in reactive astrogliosis. Enhanced NEK6 expression promotes reactive astrogliosis and exacerbates brain lesions; and conversely, NEK6 downregulation dampens injury-induced astrocyte reactivity and reduces lesion size. Mechanistically, NEK6 associates with and phosphorylates STAT3. Kinase activity of NEK6 is required for induction of GFAP and PCNA, markers of reactive astrogliosis. Interestingly, NEK6 is also localized in the nucleus and binds to STAT3-responsive genomic elements in astrocytes. These results indicate that NEK6 constitutes a molecular target for the regulation of reactive astrogliosis.
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Affiliation(s)
- Ying Yu
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.,Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Tianjin Shen
- Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Xiaoling Zhong
- Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Lei-Lei Wang
- Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Wenjiao Tai
- Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Yuhua Zou
- Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Jun Qin
- Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhaohui Zhang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chun-Li Zhang
- Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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Xiao M, Du C, Zhang C, Zhang X, Li S, Zhang D, Jia W. Bioinformatics analysis of the prognostic value of NEK8 and its effects on immune cell infiltration in glioma. J Cell Mol Med 2021; 25:8748-8763. [PMID: 34374193 PMCID: PMC8435421 DOI: 10.1111/jcmm.16831] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/28/2021] [Accepted: 07/15/2021] [Indexed: 12/26/2022] Open
Abstract
Glioma is the most common malignancy of the nervous system with high rates of recurrence and mortality, even after surgery. The 5‐year survival rate is only about 5%. NEK8 is involved in multiple biological processes in a variety of cancers; however, its role in glioma is still not clear. In the current study, we evaluated the prognostic value of NEK8, as well as its role in the pathogenesis of glioma. Using a bioinformatics approach and RNA‐seq data from public databases, we found that NEK8 expression is elevated in glioma tissues; we further verified this result by RT‐PCR, Western blotting and immunochemistry using clinical samples. Functional enrichment analyses of genes with correlated expression indicated that elevated NEK8 expression is associated with increased immune cell infiltration in glioma and may affect the tumour microenvironment via the regulation of DNA damage/repair. Survival analyses revealed that high levels of NEK8 are associated with a poorer prognosis; higher WHO grade, IDH status, 1p/19q codeletion, age and NEK8 were identified as an independent prognostic factor. These findings support the crucial role of NEK8 in the progression of glioma via effects on immune cell infiltration and suggest that it is a new prognostic biomarker.
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Affiliation(s)
- Meng Xiao
- Henan Key Laboratory of Neurorestoratology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China.,Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Chaoyang Du
- Henan Key Laboratory of Neurorestoratology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China
| | - Chuanbo Zhang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.,Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,Chinese Glioma Genome Atlas Network (CGGA), Beijing, China
| | - Xinzhong Zhang
- Henan Key Laboratory of Neurorestoratology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China
| | - Shaomin Li
- Henan Key Laboratory of Neurorestoratology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China.,Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Dainan Zhang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.,Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Wang Jia
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.,Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
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14
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Ding YY, Kim H, Madden K, Loftus JP, Chen GM, Allen DH, Zhang R, Xu J, Chen CH, Hu Y, Tasian SK, Tan K. Network Analysis Reveals Synergistic Genetic Dependencies for Rational Combination Therapy in Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia. Clin Cancer Res 2021; 27:5109-5122. [PMID: 34210682 DOI: 10.1158/1078-0432.ccr-21-0553] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 05/10/2021] [Accepted: 06/25/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Systems biology approaches can identify critical targets in complex cancer signaling networks to inform new therapy combinations that may overcome conventional treatment resistance. EXPERIMENTAL DESIGN We performed integrated analysis of 1,046 childhood B-ALL cases and developed a data-driven network controllability-based approach to identify synergistic key regulator targets in Philadelphia chromosome-like B-acute lymphoblastic leukemia (Ph-like B-ALL), a common high-risk leukemia subtype associated with hyperactive signal transduction and chemoresistance. RESULTS We identified 14 dysregulated network nodes in Ph-like ALL involved in aberrant JAK/STAT, Ras/MAPK, and apoptosis pathways and other critical processes. Genetic cotargeting of the synergistic key regulator pair STAT5B and BCL2-associated athanogene 1 (BAG1) significantly reduced leukemia cell viability in vitro. Pharmacologic inhibition with dual small molecule inhibitor therapy targeting this pair of key nodes further demonstrated enhanced antileukemia efficacy of combining the BCL-2 inhibitor venetoclax with the tyrosine kinase inhibitors ruxolitinib or dasatinib in vitro in human Ph-like ALL cell lines and in vivo in multiple childhood Ph-like ALL patient-derived xenograft models. Consistent with network controllability theory, co-inhibitor treatment also shifted the transcriptomic state of Ph-like ALL cells to become less like kinase-activated BCR-ABL1-rearranged (Ph+) B-ALL and more similar to prognostically favorable childhood B-ALL subtypes. CONCLUSIONS Our study represents a powerful conceptual framework for combinatorial drug discovery based on systematic interrogation of synergistic vulnerability pathways with pharmacologic inhibitor validation in preclinical human leukemia models.
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Affiliation(s)
- Yang-Yang Ding
- Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.,Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Hannah Kim
- Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, Pennsylvania
| | - Kellyn Madden
- Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Joseph P Loftus
- Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Gregory M Chen
- Graduate Group in Genomics and Computational Biology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - David Hottman Allen
- Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Ruitao Zhang
- Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Jason Xu
- Graduate Group in Genomics and Computational Biology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Chia-Hui Chen
- Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Yuxuan Hu
- School of Computer Science and Technology, Xidian University, Xi'an, Shaanxi, China
| | - Sarah K Tasian
- Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. .,Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kai Tan
- Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. .,Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.,Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
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15
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Pavan ICB, Peres de Oliveira A, Dias PRF, Basei FL, Issayama LK, Ferezin CDC, Silva FR, Rodrigues de Oliveira AL, Alves dos Reis Moura L, Martins MB, Simabuco FM, Kobarg J. On Broken Ne(c)ks and Broken DNA: The Role of Human NEKs in the DNA Damage Response. Cells 2021; 10:507. [PMID: 33673578 PMCID: PMC7997185 DOI: 10.3390/cells10030507] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/04/2021] [Accepted: 02/22/2021] [Indexed: 02/07/2023] Open
Abstract
NIMA-related kinases, or NEKs, are a family of Ser/Thr protein kinases involved in cell cycle and mitosis, centrosome disjunction, primary cilia functions, and DNA damage responses among other biological functional contexts in vertebrate cells. In human cells, there are 11 members, termed NEK1 to 11, and the research has mainly focused on exploring the more predominant roles of NEKs in mitosis regulation and cell cycle. A possible important role of NEKs in DNA damage response (DDR) first emerged for NEK1, but recent studies for most NEKs showed participation in DDR. A detailed analysis of the protein interactions, phosphorylation events, and studies of functional aspects of NEKs from the literature led us to propose a more general role of NEKs in DDR. In this review, we express that NEK1 is an activator of ataxia telangiectasia and Rad3-related (ATR), and its activation results in cell cycle arrest, guaranteeing DNA repair while activating specific repair pathways such as homology repair (HR) and DNA double-strand break (DSB) repair. For NEK2, 6, 8, 9, and 11, we found a role downstream of ATR and ataxia telangiectasia mutated (ATM) that results in cell cycle arrest, but details of possible activated repair pathways are still being investigated. NEK4 shows a connection to the regulation of the nonhomologous end-joining (NHEJ) repair of DNA DSBs, through recruitment of DNA-PK to DNA damage foci. NEK5 interacts with topoisomerase IIβ, and its knockdown results in the accumulation of damaged DNA. NEK7 has a regulatory role in the detection of oxidative damage to telomeric DNA. Finally, NEK10 has recently been shown to phosphorylate p53 at Y327, promoting cell cycle arrest after exposure to DNA damaging agents. In summary, this review highlights important discoveries of the ever-growing involvement of NEK kinases in the DDR pathways. A better understanding of these roles may open new diagnostic possibilities or pharmaceutical interventions regarding the chemo-sensitizing inhibition of NEKs in various forms of cancer and other diseases.
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Affiliation(s)
- Isadora Carolina Betim Pavan
- Graduate Program in “Ciências Farmacêuticas”, School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, State University of Campinas (UNICAMP), R. Cândido Portinari 200, Prédio 2, Campinas CEP 13083-871, Brazil; (I.C.B.P.); (A.P.d.O.); (P.R.F.D.); (F.L.B.); (L.K.I.); (F.R.S.); (A.L.R.d.O.); (L.A.d.R.M.); (M.B.M.)
| | - Andressa Peres de Oliveira
- Graduate Program in “Ciências Farmacêuticas”, School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, State University of Campinas (UNICAMP), R. Cândido Portinari 200, Prédio 2, Campinas CEP 13083-871, Brazil; (I.C.B.P.); (A.P.d.O.); (P.R.F.D.); (F.L.B.); (L.K.I.); (F.R.S.); (A.L.R.d.O.); (L.A.d.R.M.); (M.B.M.)
| | - Pedro Rafael Firmino Dias
- Graduate Program in “Ciências Farmacêuticas”, School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, State University of Campinas (UNICAMP), R. Cândido Portinari 200, Prédio 2, Campinas CEP 13083-871, Brazil; (I.C.B.P.); (A.P.d.O.); (P.R.F.D.); (F.L.B.); (L.K.I.); (F.R.S.); (A.L.R.d.O.); (L.A.d.R.M.); (M.B.M.)
| | - Fernanda Luisa Basei
- Graduate Program in “Ciências Farmacêuticas”, School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, State University of Campinas (UNICAMP), R. Cândido Portinari 200, Prédio 2, Campinas CEP 13083-871, Brazil; (I.C.B.P.); (A.P.d.O.); (P.R.F.D.); (F.L.B.); (L.K.I.); (F.R.S.); (A.L.R.d.O.); (L.A.d.R.M.); (M.B.M.)
| | - Luidy Kazuo Issayama
- Graduate Program in “Ciências Farmacêuticas”, School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, State University of Campinas (UNICAMP), R. Cândido Portinari 200, Prédio 2, Campinas CEP 13083-871, Brazil; (I.C.B.P.); (A.P.d.O.); (P.R.F.D.); (F.L.B.); (L.K.I.); (F.R.S.); (A.L.R.d.O.); (L.A.d.R.M.); (M.B.M.)
| | - Camila de Castro Ferezin
- Graduate Program in “Biologia Funcional e Molecular”, Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas 13083-857, Brazil;
| | - Fernando Riback Silva
- Graduate Program in “Ciências Farmacêuticas”, School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, State University of Campinas (UNICAMP), R. Cândido Portinari 200, Prédio 2, Campinas CEP 13083-871, Brazil; (I.C.B.P.); (A.P.d.O.); (P.R.F.D.); (F.L.B.); (L.K.I.); (F.R.S.); (A.L.R.d.O.); (L.A.d.R.M.); (M.B.M.)
| | - Ana Luisa Rodrigues de Oliveira
- Graduate Program in “Ciências Farmacêuticas”, School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, State University of Campinas (UNICAMP), R. Cândido Portinari 200, Prédio 2, Campinas CEP 13083-871, Brazil; (I.C.B.P.); (A.P.d.O.); (P.R.F.D.); (F.L.B.); (L.K.I.); (F.R.S.); (A.L.R.d.O.); (L.A.d.R.M.); (M.B.M.)
| | - Lívia Alves dos Reis Moura
- Graduate Program in “Ciências Farmacêuticas”, School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, State University of Campinas (UNICAMP), R. Cândido Portinari 200, Prédio 2, Campinas CEP 13083-871, Brazil; (I.C.B.P.); (A.P.d.O.); (P.R.F.D.); (F.L.B.); (L.K.I.); (F.R.S.); (A.L.R.d.O.); (L.A.d.R.M.); (M.B.M.)
| | - Mariana Bonjiorno Martins
- Graduate Program in “Ciências Farmacêuticas”, School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, State University of Campinas (UNICAMP), R. Cândido Portinari 200, Prédio 2, Campinas CEP 13083-871, Brazil; (I.C.B.P.); (A.P.d.O.); (P.R.F.D.); (F.L.B.); (L.K.I.); (F.R.S.); (A.L.R.d.O.); (L.A.d.R.M.); (M.B.M.)
- Graduate Program in “Biologia Funcional e Molecular”, Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas 13083-857, Brazil;
| | | | - Jörg Kobarg
- Graduate Program in “Ciências Farmacêuticas”, School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, State University of Campinas (UNICAMP), R. Cândido Portinari 200, Prédio 2, Campinas CEP 13083-871, Brazil; (I.C.B.P.); (A.P.d.O.); (P.R.F.D.); (F.L.B.); (L.K.I.); (F.R.S.); (A.L.R.d.O.); (L.A.d.R.M.); (M.B.M.)
- Graduate Program in “Biologia Funcional e Molecular”, Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas 13083-857, Brazil;
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Xu X, Li M, Deng Z, Hu J, Jiang Z, Liu Y, Chang K, Hu C. Grass Carp ( Ctenopharyngodon idellus) NIMA-Related Kinase 6 Blocks dsRNA-Induced IFN I Response by Targeting IRF3. Front Immunol 2021; 11:597775. [PMID: 33488591 PMCID: PMC7820699 DOI: 10.3389/fimmu.2020.597775] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 11/25/2020] [Indexed: 02/05/2023] Open
Abstract
Accumulating evidence indicates that mammalian NIMA (never in mitosis, gene A)-related kinase 6 (NEK6) plays potential roles during the course of tumorigenesis, but little is known about NEK6 in lower vertebrates. Herein, we reported a mammalian ortholog of NEK6 in grass carp (Ctenopharyngodon idellus) (CiNEK6). Multiple alignment of amino acid sequences and phylogenetic analysis showed that CiNEK6 shares a high level of sequence similarity with its counterparts in birds. CiNEK6 was ubiquitously expressed in all tested tissues, and its expression level was increased under treatment with GCRV (dsRNA virus) or poly I:C (dsRNA analog). Q-PCR and dual-luciferase assays suggested that CiNEK6 overexpression suppressed IFN I activity in CIK cells treated with poly I:C. Knockdown of CiNEK6 resulted in a higher level of IFN I expression in CIK cells treated with poly I:C compared to those which received PBS. Interestingly, analysis of subcellular localization demonstrated that CiNEK6 protein scattered throughout the cytoplasm is gradually congregated together at the edges of karyotheca upon stimulation with poly I:C. Co-IP and co-localization assays suggested that CiNEK6 interacts with CiIRF3 after poly I:C challenge. In poly I:C-treated cells, the phosphorylation of CiIRF3 was increased by CiNEK6 knockdown, but was suppressed by CiNEK6 overexpression, suggesting that CiNEK6 decreases IFN I expression through inhibiting CiIRF3 activity. Cell viability assay, crystal violet staining, and detection of Vp5 also showed that CiNEK6 plays an inhibitory role in IRF3-mediated antiviral responses.
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Affiliation(s)
- Xiaowen Xu
- College of Life Science, Nanchang University, Nanchang, China
| | - Meifeng Li
- College of Life Science, Nanchang University, Nanchang, China
| | - Zeyuan Deng
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| | - Jihuan Hu
- College of Life Science, Nanchang University, Nanchang, China
| | - Zeyin Jiang
- College of Life Science, Nanchang University, Nanchang, China
| | - Yapeng Liu
- College of Life Science, Nanchang University, Nanchang, China
| | - Kaile Chang
- College of Life Science, Nanchang University, Nanchang, China
| | - Chengyu Hu
- College of Life Science, Nanchang University, Nanchang, China
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Roberts V, Main B, Timpson NJ, Haworth S. Genome-Wide Association Study Identifies Genetic Associations with Perceived Age. J Invest Dermatol 2020; 140:2380-2385. [PMID: 32339537 PMCID: PMC7685007 DOI: 10.1016/j.jid.2020.03.970] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 02/28/2020] [Accepted: 03/04/2020] [Indexed: 11/20/2022]
Abstract
Failure of dermal protection or repair mechanisms might lead to visibly aged skin. The study aimed to identify genetic associations with perceived age. A genome-wide association study was undertaken in 423,992 adult participants of UK Biobank, using questionnaire data on perceived age and genetic data imputed to the Haplotype Reference Consortium imputation panel. The study identified 74 independently associated genetic loci, to our knowledge previously unreported (P < 5 × 10-8), which were enriched for cell signaling pathways, including the NEK6 and SMAD2 subnetworks. Common genetic variation was estimated to account for 14% of variation in perceived age, and the heritability of perceived age was partially shared with that of 75 other traits, including multiple traits representing adiposity, suggesting that perceived age may be a useful proxy trait in genetic association studies.
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Affiliation(s)
- Victoria Roberts
- Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Barry Main
- Bristol Medical School, University of Bristol, Bristol, United Kingdom; Bristol Dental School, University of Bristol, Bristol, United Kingdom
| | - Nicholas J Timpson
- MRC Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Simon Haworth
- Bristol Dental School, University of Bristol, Bristol, United Kingdom; MRC Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
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18
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NEK10 tyrosine phosphorylates p53 and controls its transcriptional activity. Oncogene 2020; 39:5252-5266. [DOI: 10.1038/s41388-020-1361-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 06/02/2020] [Accepted: 06/08/2020] [Indexed: 11/09/2022]
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19
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Barabutis N. Regulation of lung endothelial permeability by NEK kinases. IUBMB Life 2020; 72:801-804. [PMID: 32045095 DOI: 10.1002/iub.2251] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 01/29/2020] [Indexed: 01/18/2023]
Abstract
Dysregulation of lung endothelial barrier function may lead to lethal outcomes, as demonstrated in the case of the acute respiratory distress syndrome (ARDS). p53 participates in the regulation of the lung endothelial barrier, and it has been associated both in vivo and in vitro with protective effects against the LPS-induced hyperpermeability. Family members of the never in mitosis A-related kinases (NEKs) are crucial mediators of fundamental cellular processes, including mitosis, and have been shown to posttranslationally modify p53. Since such modifications affect p53 stability and activity, it is highly probable that NEK kinases are also regulators of lung endothelial permeability. Thus, they may serve as possible therapeutic targets for treatment of pathologies associated with endothelial barrier dysfunction.
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Affiliation(s)
- Nektarios Barabutis
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, Louisiana, USA
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20
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Zhang C, Sheng J, Li G, Zhao L, Wang Y, Yang W, Yao X, Sun L, Zhang Z, Cui R. Effects of Berberine and Its Derivatives on Cancer: A Systems Pharmacology Review. Front Pharmacol 2020; 10:1461. [PMID: 32009943 PMCID: PMC6974675 DOI: 10.3389/fphar.2019.01461] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 11/13/2019] [Indexed: 12/15/2022] Open
Abstract
Numerous studies have shown that berberine and its derivatives demonstrate important anti-tumor effects. However, the specific underlying mechanism remains unclear. Therefore, based on systems pharmacology, this review summarizes the information available on the anti-tumor effects and mechanism of berberine and its derivatives. The action and potential mechanism of action of berberine and its derivatives when used in the treatment of complex cancers are systematically examined at the molecular, cellular, and organismic levels. It is concluded that, with further in-depth investigations on their toxicity and efficacy, berberine and its derivatives have the potential for use as drugs in cancer therapy, offering improved clinical efficacy and safety.
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Affiliation(s)
- Chaohe Zhang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, Second Hospital of Jilin University, Changchun, China
| | - Jiyao Sheng
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, Second Hospital of Jilin University, Changchun, China
| | - Guangquan Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, Second Hospital of Jilin University, Changchun, China
| | - Lihong Zhao
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, Second Hospital of Jilin University, Changchun, China
| | - Yicun Wang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, Second Hospital of Jilin University, Changchun, China
| | - Wei Yang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, Second Hospital of Jilin University, Changchun, China
| | - Xiaoxiao Yao
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, Second Hospital of Jilin University, Changchun, China
| | - Lihuan Sun
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, Second Hospital of Jilin University, Changchun, China
| | - Zhuo Zhang
- China-Japan Union Hospital of Jilin University, Changchun, China
| | - Ranji Cui
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, Second Hospital of Jilin University, Changchun, China
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21
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Kim YY, Um JH, Yoon JH, Lee DY, Lee YJ, Kim DH, Park JI, Yun J. p53 regulates mitochondrial dynamics by inhibiting Drp1 translocation into mitochondria during cellular senescence. FASEB J 2019; 34:2451-2464. [PMID: 31908078 DOI: 10.1096/fj.201901747rr] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 11/21/2019] [Accepted: 12/03/2019] [Indexed: 01/05/2023]
Abstract
Cellular senescence acts as an important barrier to tumorigenesis by eliminating precancerous cells. Previous studies have shown an essential role of the tumor suppressor p53 in cellular senescence, but how p53 induces cellular senescence is not fully understood. We found that p53 promoted the formation of highly interconnected and elongated mitochondria prior to the onset of cellular senescence. The inhibition of mitochondrial elongation upon p53 expression suppressed cellular senescence, suggesting that mitochondrial elongation is required for the induction of p53-dependent senescence. p53-induced mitochondrial elongation resulted in mitochondrial dysfunction and subsequent increases in intracellular reactive oxygen species (ROS) levels, an important mediator of cellular senescence. Mechanistically, the inhibitory phosphorylation of Drp1 Ser637 increased upon p53 expression, suppressing the translocation of Drp1 into mitochondria. The transcriptional function of p53 was crucial for controlling the inhibitory phosphorylation of Drp1, whereas p21 was nonessential. Protein kinase A (PKA) activity was responsible for p53-mediated Drp1 Ser637 phosphorylation and mitochondrial dysfunction. Taken together, these results suggest that p53 regulates mitochondrial dynamics through the PKA-Drp1 pathway to induce cellular senescence.
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Affiliation(s)
- Young Yeon Kim
- Peripheral Neuropathy Research Center, Dong-A University, Busan, Republic of Korea.,Department of Biochemistry, College of Medicine, Dong-A University, Busan, Republic of Korea
| | - Jee-Hyun Um
- Peripheral Neuropathy Research Center, Dong-A University, Busan, Republic of Korea.,Department of Biochemistry, College of Medicine, Dong-A University, Busan, Republic of Korea
| | - Jeong-Hyun Yoon
- Peripheral Neuropathy Research Center, Dong-A University, Busan, Republic of Korea.,Department of Biochemistry, College of Medicine, Dong-A University, Busan, Republic of Korea
| | - Da-Ye Lee
- Peripheral Neuropathy Research Center, Dong-A University, Busan, Republic of Korea.,Department of Biochemistry, College of Medicine, Dong-A University, Busan, Republic of Korea
| | - Yoon Jung Lee
- Peripheral Neuropathy Research Center, Dong-A University, Busan, Republic of Korea.,Department of Biochemistry, College of Medicine, Dong-A University, Busan, Republic of Korea
| | - Dong Hyun Kim
- Peripheral Neuropathy Research Center, Dong-A University, Busan, Republic of Korea.,Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, Republic of Korea
| | - Joo-In Park
- Peripheral Neuropathy Research Center, Dong-A University, Busan, Republic of Korea.,Department of Biochemistry, College of Medicine, Dong-A University, Busan, Republic of Korea
| | - Jeanho Yun
- Peripheral Neuropathy Research Center, Dong-A University, Busan, Republic of Korea.,Department of Biochemistry, College of Medicine, Dong-A University, Busan, Republic of Korea
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22
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He Z, Ni X, Xia L, Shao Z. Overexpression of NIMA-related kinase 6 (NEK6) contributes to malignant growth and dismal prognosis in Human Breast Cancer. Pathol Res Pract 2018; 214:1648-1654. [PMID: 30153958 DOI: 10.1016/j.prp.2018.07.030] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Revised: 07/16/2018] [Accepted: 07/25/2018] [Indexed: 12/16/2022]
Abstract
NIMA Related Kinase 6 (Nek6) is a protein kinase involved in various cellular processes, including cell cycle regulation, apopotosis, senescence, telomere maintainance and chemoresistance. In the present study, we investigated the role of Nek6 in breast tumorigenesis and the prognostic merit of Nek6 expression in breast cancer. Immunohistochemistry and Western blot analyses was conducted to determine the expression profile of Nek6 in 133 breast cancer specimens. Nek6 was overexpressed in a majority of breast cancer specimens, compared with the adjacent non-tumorous tissues. Furthermore, we revealed that high expression of Nek6 was associated with histologic grade, tumor size and TNM stage in breast cancer. Liner regression analysis showed a significant association between the levels of Nek6 and Ki-67. Cox regression analysis indicated that Nek6 expression was an independent prognostic predictor for breast cancer. Moreover, intracellular level of Nek6 was remarkably increased following the release from serum starvation in MCF-7 cells. EdU incorporation assay indicated that depletion of Nek6 remarkably impaired the proliferation of MCF-7 cells. Finally, spheroid formation assay revealed that interference of Nek6 led to diminished oncospheroid-forming capacity of breast cancer cells. In conclusion, our results imply that Nek6 plays a facilitating role in breast cancer cell proliferation and may serve as a promising therapeutic target for breast cancer.
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Affiliation(s)
- Zhixian He
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, PR China; Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu, PR China
| | - Xiaojian Ni
- Department of General Surgery, Fudan University Zhongshan Hospital, Shanghai 200032, PR China
| | - Liuwan Xia
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu, PR China
| | - Zhimin Shao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, PR China.
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23
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Biray Avci C, Goker Bagca B, Tetik Vardarli A, Saydam G, Gunduz C. Epigenetic modifications in chronic myeloid leukemia cells through ruxolitinib treatment. J Cell Biochem 2018; 120:4555-4563. [PMID: 30260022 DOI: 10.1002/jcb.27744] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 08/31/2018] [Indexed: 12/28/2022]
Abstract
Chronic myeloid leukemia is a clonal malignancy of hematopoietic stem cell that is characterized by the occurrence of t(9;22)(q34;q11.2) translocation, named Philadelphia chromosome. Ruxolitinib is a powerful Janus tyrosine kinase 1 and 2 inhibitor that is used for myelofibrosis treatment. DNA-histone connection mediates a wide range of genes that code methylation, demethylation, acetylation, deacetylation, ubiquitination, and phosphorylation enzymes. Epigenetic modifications regulate chromatin compactness, which plays pivotal roles in critical biological processes including the transcriptional activity and cell proliferation as well as various pathological mechanisms, including CML. This study is aimed to determine the alterations of the expression levels of epigenetic modification-related genes after ruxolitinib treatment. Total RNA was isolated from K-562 cells treated with the IC50 value of ruxolitinib and untreated K-562 control cells. A reverse transcription procedure was performed for complementary DNA synthesis, and gene expressions were detected by real-time polymerase chain reaction compared with the untreated cells. Ruxolitinib treatment caused a significant alteration in the expression levels of epigenetic regulation-related genes in K-562 cells. Our novel results suggested that ruxolitinib has inhibitor effects on epigenetic modification-regulator genes.
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Affiliation(s)
- Cigir Biray Avci
- Department of Medical Biology, Medical Faculty, Ege University, Izmir, Turkey
| | - Bakiye Goker Bagca
- Department of Medical Biology, Medical Faculty, Ege University, Izmir, Turkey
| | - Asli Tetik Vardarli
- Department of Medical Biology, Medical Faculty, Ege University, Izmir, Turkey
| | - Guray Saydam
- Department of Internal Medicine, Division of Haematology, Medical Faculty, Ege University, Izmir, Turkey
| | - Cumhur Gunduz
- Department of Medical Biology, Medical Faculty, Ege University, Izmir, Turkey
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24
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McCubrey JA, Lertpiriyapong K, Steelman LS, Abrams SL, Yang LV, Murata RM, Rosalen PL, Scalisi A, Neri LM, Cocco L, Ratti S, Martelli AM, Laidler P, Dulińska-Litewka J, Rakus D, Gizak A, Lombardi P, Nicoletti F, Candido S, Libra M, Montalto G, Cervello M. Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs. Aging (Albany NY) 2018; 9:1477-1536. [PMID: 28611316 PMCID: PMC5509453 DOI: 10.18632/aging.101250] [Citation(s) in RCA: 134] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 06/04/2017] [Indexed: 02/07/2023]
Abstract
Natural products or nutraceuticals have been shown to elicit anti-aging, anti-cancer and other health-enhancing effects. A key target of the effects of natural products may be the regulation of microRNA (miR) expression which results in cell death or prevents aging, diabetes, cardiovascular and other diseases. This review will focus on a few natural products, especially on resveratrol (RES), curcumin (CUR) and berberine (BBR). RES is obtained from the skins of grapes and other fruits and berries. RES may extend human lifespan by activating the sirtuins and SIRT1 molecules. CUR is isolated from the root of turmeric (Curcuma longa). CUR is currently used in the treatment of many disorders, especially in those involving an inflammatory process. CUR and modified derivatives have been shown to have potent anti-cancer effects, especially on cancer stem cells (CSC). BBR is also isolated from various plants (e.g., Coptis chinensis) and has been used for centuries in traditional medicine to treat diseases such as adult- onset diabetes. Understanding the benefits of these and other nutraceuticals may result in approaches to improve human health.
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Affiliation(s)
- James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Kvin Lertpiriyapong
- Department of Comparative Medicine, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Linda S Steelman
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Steve L Abrams
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Li V Yang
- Department of Internal Medicine, Hematology/Oncology Section, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Ramiro M Murata
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.,Department of Foundational Sciences, School of Dental Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Pedro L Rosalen
- Department of Physiological Sciences, Piracicaba Dental School, State University of Campinas, Piracicaba, Brazil
| | - Aurora Scalisi
- Unit of Oncologic Diseases, ASP-Catania, Catania 95100, Italy
| | - Luca M Neri
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Lucio Cocco
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Stefano Ratti
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Alberto M Martelli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Piotr Laidler
- Chair of Medical Biochemistry, Jagiellonian University Medical College, Kraków, Poland
| | | | - Dariusz Rakus
- Department of Animal Molecular Physiology and Neurobiology, Wroclaw University, Wroclaw, Poland
| | - Agnieszka Gizak
- Department of Animal Molecular Physiology and Neurobiology, Wroclaw University, Wroclaw, Poland
| | | | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy
| | - Saverio Candido
- Department of Biomedical and Biotechnological Sciences, Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy
| | - Giuseppe Montalto
- Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy.,Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Melchiorre Cervello
- Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
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25
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Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy. Mediators Inflamm 2018; 2018:4159013. [PMID: 29618945 PMCID: PMC5829354 DOI: 10.1155/2018/4159013] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 12/19/2017] [Indexed: 12/18/2022] Open
Abstract
The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2) pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune-depressed organisms) that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin) on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity.
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26
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Fry AM, Bayliss R, Roig J. Mitotic Regulation by NEK Kinase Networks. Front Cell Dev Biol 2017; 5:102. [PMID: 29250521 PMCID: PMC5716973 DOI: 10.3389/fcell.2017.00102] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 11/17/2017] [Indexed: 12/24/2022] Open
Abstract
Genetic studies in yeast and Drosophila led to identification of cyclin-dependent kinases (CDKs), Polo-like kinases (PLKs) and Aurora kinases as essential regulators of mitosis. These enzymes have since been found in the majority of eukaryotes and their cell cycle-related functions characterized in great detail. However, genetic studies in another fungal species, Aspergillus nidulans, identified a distinct family of protein kinases, the NEKs, that are also widely conserved and have key roles in the cell cycle, but which remain less well studied. Nevertheless, it is now clear that multiple NEK family members act in networks to regulate specific events of mitosis, including centrosome separation, spindle assembly and cytokinesis. Here, we describe our current understanding of how the NEK kinases contribute to these processes, particularly through targeted phosphorylation of proteins associated with the microtubule cytoskeleton. We also present the latest findings on molecular events that control the activation state of the NEKs and how these are revealing novel modes of enzymatic regulation relevant not only to other kinases but also to pathological mechanisms of disease.
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Affiliation(s)
- Andrew M. Fry
- Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom
| | - Richard Bayliss
- School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom
| | - Joan Roig
- Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Barcelona, Spain
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27
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Kim YY, Jee HJ, Um JH, Kim YM, Bae SS, Yun J. Cooperation between p21 and Akt is required for p53-dependent cellular senescence. Aging Cell 2017; 16:1094-1103. [PMID: 28691365 PMCID: PMC5595696 DOI: 10.1111/acel.12639] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/04/2017] [Indexed: 12/30/2022] Open
Abstract
Cellular senescence has been implicated in normal aging, tissue homeostasis, and tumor suppression. Although p53 has been shown to be a central mediator of cellular senescence, the signaling pathway by which it induces senescence remains incompletely understood. In this study, we have shown that both Akt and p21 are required to induce cellular senescence in response to p53 expression. In a p53-induced senescence model, we found that Akt activation was essential for inducing a cellular senescence phenotype. Surprisingly, Akt inhibition did not abolish p53-induced cell cycle arrest, but it suppressed the increase in intracellular reactive oxygen species (ROS) levels. The results of the cell cycle and morphological analysis suggest that p53 induced quiescence, not senescence, following Akt inhibition. Conversely, the inhibition of p21 induction abolished cell cycle arrest but did not affect the p53-induced increase in ROS levels. Additionally, p21 and Akt separately controlled cell cycle arrest and ROS levels, respectively, during H-Ras-induced senescence in human normal fibroblasts. The mechanistic analysis revealed that Akt increased ROS levels through NOX4 induction, and increased Akt-dependent NF-κB binding to the NOX4 promoter is responsible for NOX4 induction upon p53 expression. We further showed that Akt activation upon p53 expression is mediated by mammalian target of rapamycin complex 2. In addition, p53-mediated IL6 and IL8 induction was abrogated by Akt inhibition, suggesting that Akt activation is also required for the senescence-associated secretory phenotype. Collectively, these results suggest that p53 simultaneously controls multiple pathways to induce cellular senescence through p21 and Akt.
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Affiliation(s)
- Young Yeon Kim
- Peripheral Neuropathy Research Center; College of Medicine; Dong-A University; Busan 49201 Korea
- Department of Biochemistry; College of Medicine; Dong-A University; Busan 49201 Korea
| | - Hye Jin Jee
- Peripheral Neuropathy Research Center; College of Medicine; Dong-A University; Busan 49201 Korea
- Department of Biochemistry; College of Medicine; Dong-A University; Busan 49201 Korea
| | - Jee-Hyun Um
- Peripheral Neuropathy Research Center; College of Medicine; Dong-A University; Busan 49201 Korea
- Department of Biochemistry; College of Medicine; Dong-A University; Busan 49201 Korea
| | - Young Mi Kim
- Peripheral Neuropathy Research Center; College of Medicine; Dong-A University; Busan 49201 Korea
- Department of Biochemistry; College of Medicine; Dong-A University; Busan 49201 Korea
| | - Sun Sik Bae
- Department of Pharmacology; School of Medicine; Pusan National University; Yangsan-si 602-739 Korea
| | - Jeanho Yun
- Peripheral Neuropathy Research Center; College of Medicine; Dong-A University; Busan 49201 Korea
- Department of Biochemistry; College of Medicine; Dong-A University; Busan 49201 Korea
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28
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Li CQ, Huang GW, Wu ZY, Xu YJ, Li XC, Xue YJ, Zhu Y, Zhao JM, Li M, Zhang J, Wu JY, Lei F, Wang QY, Li S, Zheng CP, Ai B, Tang ZD, Feng CC, Liao LD, Wang SH, Shen JH, Liu YJ, Bai XF, He JZ, Cao HH, Wu BL, Wang MR, Lin DC, Koeffler HP, Wang LD, Li X, Li EM, Xu LY. Integrative analyses of transcriptome sequencing identify novel functional lncRNAs in esophageal squamous cell carcinoma. Oncogenesis 2017; 6:e297. [PMID: 28194033 PMCID: PMC5337622 DOI: 10.1038/oncsis.2017.1] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Revised: 12/17/2016] [Accepted: 12/23/2016] [Indexed: 02/05/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) have a critical role in cancer initiation and progression, and thus may mediate oncogenic or tumor suppressing effects, as well as be a new class of cancer therapeutic targets. We performed high-throughput sequencing of RNA (RNA-seq) to investigate the expression level of lncRNAs and protein-coding genes in 30 esophageal samples, comprised of 15 esophageal squamous cell carcinoma (ESCC) samples and their 15 paired non-tumor tissues. We further developed an integrative bioinformatics method, denoted URW-LPE, to identify key functional lncRNAs that regulate expression of downstream protein-coding genes in ESCC. A number of known onco-lncRNA and many putative novel ones were effectively identified by URW-LPE. Importantly, we identified lncRNA625 as a novel regulator of ESCC cell proliferation, invasion and migration. ESCC patients with high lncRNA625 expression had significantly shorter survival time than those with low expression. LncRNA625 also showed specific prognostic value for patients with metastatic ESCC. Finally, we identified E1A-binding protein p300 (EP300) as a downstream executor of lncRNA625-induced transcriptional responses. These findings establish a catalog of novel cancer-associated functional lncRNAs, which will promote our understanding of lncRNA-mediated regulation in this malignancy.
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Affiliation(s)
- C-Q Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - G-W Huang
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
| | - Z-Y Wu
- Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou, China
| | - Y-J Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - X-C Li
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - Y-J Xue
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
| | - Y Zhu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
| | - J-M Zhao
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - M Li
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - J Zhang
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - J-Y Wu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
| | - F Lei
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
| | - Q-Y Wang
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - S Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - C-P Zheng
- Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou, China
| | - B Ai
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - Z-D Tang
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - C-C Feng
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - L-D Liao
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
| | - S-H Wang
- Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou, China
| | - J-H Shen
- Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou, China
| | - Y-J Liu
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - X-F Bai
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - J-Z He
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
| | - H-H Cao
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
| | - B-L Wu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
| | - M-R Wang
- Cancer Institute/Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - D-C Lin
- Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA
| | - H P Koeffler
- Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- National University Cancer Institute of Singapore, National University Health System and National University Hospital, Singapore, Singapore
| | - L-D Wang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - X Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. E-mail:
| | - E-M Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, No. 22, Xinling Road, Shantou, Guangdong 515041, China. E-mail:
| | - L-Y Xu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, No. 22, Xinling Road, Shantou, Guangdong 515041, China. E-mail:
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Choudhury AD, Schinzel AC, Cotter MB, Lis RT, Labella K, Lock YJ, Izzo F, Guney I, Bowden M, Li YY, Patel J, Hartman E, Carr SA, Schenone M, Jaffe JD, Kantoff PW, Hammerman PS, Hahn WC. Castration Resistance in Prostate Cancer Is Mediated by the Kinase NEK6. Cancer Res 2017; 77:753-765. [PMID: 27899381 PMCID: PMC5290202 DOI: 10.1158/0008-5472.can-16-0455] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 10/09/2016] [Accepted: 11/04/2016] [Indexed: 01/16/2023]
Abstract
In prostate cancer, the development of castration resistance is pivotal in progression to aggressive disease. However, understanding of the pathways involved remains incomplete. In this study, we performed a high-throughput genetic screen to identify kinases that enable tumor formation by androgen-dependent prostate epithelial (LHSR-AR) cells under androgen-deprived conditions. In addition to the identification of known mediators of castration resistance, which served to validate the screen, we identified a mitotic-related serine/threonine kinase, NEK6, as a mediator of androgen-independent tumor growth. NEK6 was overexpressed in a subset of human prostate cancers. Silencing NEK6 in castration-resistant cancer cells was sufficient to restore sensitivity to castration in a mouse xenograft model system. Tumors in which castration resistance was conferred by NEK6 were predominantly squamous in histology with no evidence of AR signaling. Gene expression profiling suggested that NEK6 overexpression stimulated cytoskeletal, differentiation, and immune signaling pathways and maintained gene expression patterns normally decreased by castration. Phosphoproteome profiling revealed the transcription factor FOXJ2 as a novel NEK6 substrate, with FOXJ2 phosphorylation associated with increased expression of newly identified NEK6 transcriptional targets. Overall, our studies establish NEK6 signaling as a central mechanism mediating castration-resistant prostate cancer. Cancer Res; 77(3); 753-65. ©2016 AACR.
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Affiliation(s)
- Atish D Choudhury
- Dana-Farber Cancer Institute, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - Anna C Schinzel
- Dana-Farber Cancer Institute, Boston, Massachusetts
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | | | - Rosina T Lis
- Dana-Farber Cancer Institute, Boston, Massachusetts
- Brigham and Women's Hospital, Boston, Massachusetts
| | | | | | - Francesca Izzo
- Dana-Farber Cancer Institute, Boston, Massachusetts
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - Isil Guney
- Dana-Farber Cancer Institute, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | | | - Yvonne Y Li
- Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jinal Patel
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - Emily Hartman
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - Steven A Carr
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - Monica Schenone
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - Jacob D Jaffe
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - Philip W Kantoff
- Dana-Farber Cancer Institute, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Peter S Hammerman
- Dana-Farber Cancer Institute, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - William C Hahn
- Dana-Farber Cancer Institute, Boston, Massachusetts.
- Harvard Medical School, Boston, Massachusetts
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
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Kooi IE, Mol BM, Massink MPG, de Jong MC, de Graaf P, van der Valk P, Meijers-Heijboer H, Kaspers GJL, Moll AC, te Riele H, Cloos J, Dorsman JC. A Meta-Analysis of Retinoblastoma Copy Numbers Refines the List of Possible Driver Genes Involved in Tumor Progression. PLoS One 2016; 11:e0153323. [PMID: 27115612 PMCID: PMC4846005 DOI: 10.1371/journal.pone.0153323] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 03/28/2016] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND While RB1 loss initiates retinoblastoma development, additional somatic copy number alterations (SCNAs) can drive tumor progression. Although SCNAs have been identified with good concordance between studies at a cytoband resolution, accurate identification of single genes for all recurrent SCNAs is still challenging. This study presents a comprehensive meta-analysis of genome-wide SCNAs integrated with gene expression profiling data, narrowing down the list of plausible retinoblastoma driver genes. METHODS We performed SCNA profiling of 45 primary retinoblastoma samples and eight retinoblastoma cell lines by high-resolution microarrays. We combined our data with genomic, clinical and histopathological data of ten published genome-wide SCNA studies, which strongly enhanced the power of our analyses (N = 310). RESULTS Comprehensive recurrence analysis of SCNAs in all studies integrated with gene expression data allowed us to reduce candidate gene lists for 1q, 2p, 6p, 7q and 13q to a limited gene set. Besides the well-established driver genes RB1 (13q-loss) and MYCN (2p-gain) we identified CRB1 and NEK7 (1q-gain), SOX4 (6p-gain) and NUP205 (7q-gain) as novel retinoblastoma driver candidates. Depending on the sample subset and algorithms used, alternative candidates were identified including MIR181 (1q-gain) and DEK (6p gain). Remarkably, our study showed that copy number gains rarely exceeded change of one copy, even in pure tumor samples with 100% homozygosity at the RB1 locus (N = 34), which is indicative for intra-tumor heterogeneity. In addition, profound between-tumor variability was observed that was associated with age at diagnosis and differentiation grades. INTERPRETATION Since focal alterations at commonly altered chromosome regions were rare except for 2p24.3 (MYCN), further functional validation of the oncogenic potential of the described candidate genes is now required. For further investigations, our study provides a refined and revised set of candidate retinoblastoma driver genes.
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Affiliation(s)
- Irsan E. Kooi
- Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
| | - Berber M. Mol
- Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
| | - Maarten P. G. Massink
- Department of Bio-medical Genetics, University Medical center Utrecht, Utrecht, The Netherlands
| | - Marcus C. de Jong
- Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Pim de Graaf
- Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Paul van der Valk
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
| | - Hanne Meijers-Heijboer
- Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
| | - Gertjan J. L. Kaspers
- Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands
| | - Annette C. Moll
- Department of Ophthalmology, VU University Medical Center, Amsterdam, the Netherlands
| | - Hein te Riele
- Division of Biological Stress Response, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jacqueline Cloos
- Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands
- Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands
| | - Josephine C. Dorsman
- Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
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Kim G, Kim JY, Choi HS. Peptidyl-Prolyl cis/trans Isomerase NIMA-Interacting 1 as a Therapeutic Target in Hepatocellular Carcinoma. Biol Pharm Bull 2016; 38:975-9. [PMID: 26133706 DOI: 10.1248/bpb.b15-00245] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Phosphorylation of proteins on serine or threonine residues preceding proline is a pivotal signaling mechanism regulating cell proliferation. The recent identification and characterization of the enzyme peptidyl-prolyl cis/trans isomerase never in mitosis A (NIMA)-interacting 1 (PIN1) has led to the discovery of a new mechanism regulating phosphorylation in cell signaling. PIN1 specifically binds phosphorylated serine or threonine residues immediately preceding proline (pSer/Thr-Pro) and then regulates protein functions, including catalytic activity, phosphorylation status, protein interactions, subcellular location, and protein stability, by promoting cis/trans isomerization of the peptide bond. Recent results have indicated that such conformational changes following phosphorylation represent a novel signaling mechanism in the regulation of many cellular functions. Understanding this mechanism also provides new insight into the pathogenesis and treatment of human hepatocellular carcinoma. A better understanding of the role of PIN1 in the pathogenesis of hepatocellular carcinoma may lead to the identification of molecular targets for prevention and therapeutic intervention.
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Affiliation(s)
- Garam Kim
- College of Pharmacy, Chosun University
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Dominguez-Brauer C, Thu KL, Mason JM, Blaser H, Bray MR, Mak TW. Targeting Mitosis in Cancer: Emerging Strategies. Mol Cell 2016; 60:524-36. [PMID: 26590712 DOI: 10.1016/j.molcel.2015.11.006] [Citation(s) in RCA: 344] [Impact Index Per Article: 38.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The cell cycle is an evolutionarily conserved process necessary for mammalian cell growth and development. Because cell-cycle aberrations are a hallmark of cancer, this process has been the target of anti-cancer therapeutics for decades. However, despite numerous clinical trials, cell-cycle-targeting agents have generally failed in the clinic. This review briefly examines past cell-cycle-targeted therapeutics and outlines how experience with these agents has provided valuable insight to refine and improve anti-mitotic strategies. An overview of emerging anti-mitotic approaches with promising pre-clinical results is provided, and the concept of exploiting the genomic instability of tumor cells through therapeutic inhibition of mitotic checkpoints is discussed. We believe this strategy has a high likelihood of success given its potential to enhance therapeutic index by targeting tumor-specific vulnerabilities. This reasoning stimulated our development of novel inhibitors targeting the critical regulators of genomic stability and the mitotic checkpoint: AURKA, PLK4, and Mps1/TTK.
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Affiliation(s)
- Carmen Dominguez-Brauer
- The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, ON M5G 2M9, Canada
| | - Kelsie L Thu
- The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, ON M5G 2M9, Canada
| | - Jacqueline M Mason
- The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada
| | - Heiko Blaser
- The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, ON M5G 2M9, Canada
| | - Mark R Bray
- The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada
| | - Tak W Mak
- The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, ON M5G 2M9, Canada.
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33
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78495111110.1016/j.molcel.2015.11.006" />
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Kasap E, Gerceker E, Boyacıoglu SÖ, Yuceyar H, Yıldırm H, Ayhan S, Korkmaz M. The potential role of the NEK6, AURKA, AURKB, and PAK1 genes in adenomatous colorectal polyps and colorectal adenocarcinoma. Tumour Biol 2015; 37:3071-80. [DOI: 10.1007/s13277-015-4131-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Accepted: 09/21/2015] [Indexed: 01/09/2023] Open
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Gerçeker E, Boyacıoglu SO, Kasap E, Baykan A, Yuceyar H, Yıldırım H, Ayhan S, Ellidokuz E, Korkmaz M. Never in mitosis gene A-related kinase 6 and aurora kinase A: New gene biomarkers in the conversion from ulcerative colitis to colorectal cancer. Oncol Rep 2015; 34:1905-14. [PMID: 26259750 DOI: 10.3892/or.2015.4187] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 07/03/2015] [Indexed: 11/06/2022] Open
Abstract
Ulcerative colitis (UC) is an important risk factor for colorectal cancer (CRC). Histone modifications are one of the epigenetic mechanisms that may have key roles in the carcinogenesis of CRC. At present, there are no studies comparing histone modification patterns of UC and CRC in the literature. Therefore the aim of the present study was to investigate whether genes, particularly those involved in histone modification, have value in patient monitoring with regards to CRC development in UC. Key gene expressions of the histone modification enzyme were assessed and compared in CRC, UC and control groups using the RT-PCR array technique. Patients were divided into subgroups based on the extent and duration of the disease and inflammatory burden, which are considered risk factors for CRC development in UC patients. In UC and CRC groups, a significantly higher overexpression of the NEK6 and AURKA genes compared to the control group was identified. In addition, there was a significantly higher overexpression of HDAC1 and PAK1 genes in the UC group, and of HDAC1, HDAC7, PAK1 and AURKB genes in the CRC group. NEK6, AURKA, HDAC1 and PAK1 were significantly overexpressed in patients with a longer UC duration. Overexpression of AURKA and NEK6 genes was significantly more pronounced in UC patients with more extensive colon involvement. HDAC1, HDAC7, PAK1, NEK6, AURKA and AURKB are important diagnostic and prognostic markers involved in the carcinogenesis of CRC. HDAC1, PAK1, NEK6 and AURKA may be considered as diagnostic markers to be used in CRC screening for UC patients.
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Affiliation(s)
- Emre Gerçeker
- Department of Gastroenterology, Medical Faculty, Celal Bayar University, Manisa, Turkey
| | - Seda Orenay Boyacıoglu
- Department of Medical Genetics and Medical Biology, Medical Faculty, Celal Bayar University, Manisa, Turkey
| | - Elmas Kasap
- Department of Gastroenterology, Medical Faculty, Celal Bayar University, Manisa, Turkey
| | - Ahmed Baykan
- Department of Gastroenterology, Medical Faculty, Celal Bayar University, Manisa, Turkey
| | - Hakan Yuceyar
- Department of Gastroenterology, Medical Faculty, Celal Bayar University, Manisa, Turkey
| | - Hatice Yıldırım
- Department of Medical Genetics and Medical Biology, Medical Faculty, Celal Bayar University, Manisa, Turkey
| | - Semin Ayhan
- Department of Pathology, Medical Faculty, Celal Bayar University, Manisa, Turkey
| | - Ender Ellidokuz
- Department of Gastroenterology, Medical Faculty, Celal Bayar University, Manisa, Turkey
| | - Mehmet Korkmaz
- Department of Medical Genetics and Medical Biology, Medical Faculty, Celal Bayar University, Manisa, Turkey
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Zuo J, Ma H, Cai H, Wu Y, Jiang W, Yu L. An inhibitory role of NEK6 in TGFβ/Smad signaling pathway. BMB Rep 2015; 48:473-478. [PMID: 25523445 PMCID: PMC4576956 DOI: 10.5483/bmbrep.2015.48.8.225] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Revised: 11/17/2014] [Accepted: 12/09/2014] [Indexed: 11/20/2022] Open
Abstract
The NEK6 (NIMA-related kinases 6) is reported to play potential roles in tumorigenesis. Although it is suggested to function in several cellular pathways, the underlying mechanism in tumorigenesis is still largely unknown. In the present study, we discovered interaction of NEK6 with Smad4, a key member of transforming growth factor beta (TGFβ) pathway. Over-expression of NEK6 in hepatocellular carcinoma (HCC) cell lines suppresses TGFβ-mediated transcription activity in a kinase activity-dependent manner. In addition, NEK6 suppresses the cell growth arrest induced by TGFβ. Mechanically, NEK6 blocks nuclear translocation of Smad4, which is essential for TGFβ function. Moreover, we identified that NEK6 could be regulated by TGFβ and hypoxia. Our study sheds new light on the roles of NEK6 in canonical TGFβ/Smad pathway and tumorigenesis.
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Affiliation(s)
- Jie Zuo
- State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai 200433, PR China
| | - Haijie Ma
- Cell and Molecular Biology Laboratory, Zhoushan Hospital, Zhejiang, China
| | - Hao Cai
- State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai 200433, PR China
| | - Yanhua Wu
- State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai 200433, PR China
| | - Wei Jiang
- State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai 200433, PR China
| | - Long Yu
- State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai 200433, PR China
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Yochem J, Lažetić V, Bell L, Chen L, Fay D. C. elegans NIMA-related kinases NEKL-2 and NEKL-3 are required for the completion of molting. Dev Biol 2015; 398:255-66. [PMID: 25523392 PMCID: PMC4314388 DOI: 10.1016/j.ydbio.2014.12.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Revised: 11/29/2014] [Accepted: 12/04/2014] [Indexed: 12/20/2022]
Abstract
Caenorhabditis elegans molting is a process during which the apical extracellular matrix of the epidermis, the cuticle, is remodeled through a process of degradation and re-synthesis. Using a genetic approach, we identified nekl-3 as essential for the completion of molting. NEKL-3 is highly similar to the mammalian NEK kinase family members NEK6 and NEK7. Animals homozygous for a hypomorphic mutation in nekl-3, sv3, had a novel molting defect in which the central body region, but not the head or tail, was unable to shed the old cuticle. In contrast, a null mutation in nekl-3, gk506, led to complete enclosure within the old cuticle. nekl-2, which is most similar to mammalian NEK8, was also essential for molting. Mosaic analyses demonstrated that NEKL-2 and NEKL-3 were specifically required within the large epidermal syncytium, hyp7, to facilitate molting. Consistent with this, NEKL-2 and NEKL-3 were expressed at the apical surface of hyp7 where they localized to small spheres or tubular structures. Inhibition of nekl-2, but not nekl-3, led to the mislocalization of LRP-1/megalin, a cell surface receptor for low-density lipoprotein (LDL)-binding proteins. In addition, nekl-2 inhibition led to the mislocalization of several other endosome-associated proteins. Notably, LRP-1 acts within hyp7 to facilitate completion of molting, suggesting at least one mechanism by which NEKL-2 may influence molting. Notably, our studies failed to reveal a requirement for NEKL-2 or NEKL-3 in cell division, a function reported for several mammalian NEKs including NEK6 and NEK7. Our findings provide the first genetic and in vivo evidence for a role of NEK family members in endocytosis, which may be evolutionarily conserved.
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Affiliation(s)
- John Yochem
- Department of Molecular Biology, College of Agriculture and Natural Resources, University of Wyoming, Laramie, WY 82071, United States; Department of Genetics, Cell Biology, and Development and the Developmental Biology Center, University of Minnesota, Minneapolis, MN 55455, United States
| | - Vladimir Lažetić
- Department of Molecular Biology, College of Agriculture and Natural Resources, University of Wyoming, Laramie, WY 82071, United States
| | - Leslie Bell
- Department of Genetics, Cell Biology, and Development and the Developmental Biology Center, University of Minnesota, Minneapolis, MN 55455, United States
| | - Lihsia Chen
- Department of Genetics, Cell Biology, and Development and the Developmental Biology Center, University of Minnesota, Minneapolis, MN 55455, United States
| | - David Fay
- Department of Molecular Biology, College of Agriculture and Natural Resources, University of Wyoming, Laramie, WY 82071, United States.
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Wang N, Zhu M, Wang X, Tan HY, Tsao SW, Feng Y. Berberine-induced tumor suppressor p53 up-regulation gets involved in the regulatory network of MIR-23a in hepatocellular carcinoma. BIOCHIMICA ET BIOPHYSICA ACTA 2014; 1839:849-857. [PMID: 24942805 DOI: 10.1016/j.bbagrm.2014.05.027] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Revised: 05/02/2014] [Accepted: 05/27/2014] [Indexed: 11/24/2022]
Abstract
AIM OF THE STUDY To investigate the involvement of p53 in the regulatory network of microRNA-23a (miR-23a) in berberine-treated hepatocellular carcinoma (HCC) cells. METHODS The biogenesis of miR-23a upon berberine treatment was monitored by detecting the transcript expression of primary precursor, precursor and mature forms of miR-23a. Protein expression was detected with immunoblotting. The binding capacity between p53 and chromatin DNA was determined by chromatin immunoprecipitation. The role of miR-23a in mediating suppression of HCC by berberine was determined both in vitro and in vivo. RESULTS miR-23a was up-regulated upon berberine treatment in human HCC cells, and berberine could increase the expression of primary precursor, precursor and mature forms of miR-23a. The up-regulation of miR-23a by berberine is p53-dependent. Inhibition of p53 expression and activity could block the up-regulation of miR-23a induced by berberine. Furthermore, berberine-induced miR-23a expression may mediate the transcription activation of p53-related tumor suppressive genes p21 and GADD45α. Inhibition of miR-23a abolishes the binding of p53 onto chromatin and attenuates transcription activation of p21 and GADD45α. Target prediction and experimental validation demonstrate that berberine-induced miR-23a may target to Nek6 to suppress its expression. Berberine-induced G2/M cell cycle arrest in HCC was attenuated when miR-23a was inhibited. Berberine-induced cell death and in vivo tumor growth inhibition are attenuated upon inhibition of miR-23a. CONCLUSION Our study reveals that miR-23a may be involved in regulating the anti-HCC effect of berberine by mediating the regulation of p53.
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Affiliation(s)
- Ning Wang
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, PR China
| | - Meifen Zhu
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, PR China
| | - Xuanbin Wang
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, PR China; Laboratory of Chinese Herbal Pharmacology, Renmin Hospital, School of Pharmacy, Hubei University of Medicine, 442000, PR China
| | - Hor-Yue Tan
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, PR China
| | - Sai-Wah Tsao
- Department of Anatomy, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, PR China
| | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, PR China.
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Li X, Lian L, Zhang D, Qu L, Yang N. gga-miR-26a targets NEK6 and suppresses Marek's disease lymphoma cell proliferation. Poult Sci 2014; 93:1097-105. [PMID: 24795301 DOI: 10.3382/ps.2013-03656] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
MicroRNA (miRNA) are a class of highly conserved, small noncoding RNA that emerge as key posttranscriptional regulators in various neoplastic transformations. Our previous study profiling the miRNA transcriptome in Marek's disease virus (MDV)-induced lymphoma revealed many novel and differentially expressed miRNA, including gga-miR-26a, which was downregulated in MDV-infected spleens of chickens. In this study, differential expression of gga-miR-26a between MDV-infected and noninfected spleens at 4, 7, 14, 21, and 28 d postinfection was analyzed by real-time PCR. The results showed gga-miR-26a were downregulated in MDV-infected spleens at cytolytic infection, latency, and tumor transformation phases. Subsequent cell proliferation assay revealed cell viability was lower in gga-miR-26a mimic transfection group than that in negative controls. Target genes of gga-miR-26a were identified by luciferase reporter gene assay. The results showed significant interaction between gga-miR-26a and Never In Mitosis Gene A (NIMA)-related kinase 6 (NEK6) gene. Subsequent gain of function experiment and Western blot assay showed that mRNA and protein levels of NEK6 were downregulated after gga-miR-26 mimic was transfected into MDV-transformed lymphoid cell line (MSB-1), indicating that NEK6 was modulated by gga-miR-26a. The expression of NEK6 showed a higher trend in MDV-infected samples including tumorous spleen and MD lymphoma from liver than that in noninfected controls. The results suggested that gga-miR-26a inhibited MSB-1 cell proliferation. Gga-miR-26a and its direct target, NEK6, might play important roles in MDV infection.
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Affiliation(s)
- Xin Li
- Department of Animal Genetics and Breeding, National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
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Meirelles GV, Perez AM, de Souza EE, Basei FL, Papa PF, Melo Hanchuk TD, Cardoso VB, Kobarg J. “Stop Ne(c)king around”: How interactomics contributes to functionally characterize Nek family kinases. World J Biol Chem 2014; 5:141-160. [PMID: 24921005 PMCID: PMC4050109 DOI: 10.4331/wjbc.v5.i2.141] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Revised: 01/07/2014] [Accepted: 02/18/2014] [Indexed: 02/05/2023] Open
Abstract
Aside from Polo and Aurora, a third but less studied kinase family involved in mitosis regulation is the never in mitosis-gene A (NIMA)-related kinases (Neks). The founding member of this family is the sole member NIMA of Aspergillus nidulans, which is crucial for the initiation of mitosis in that organism. All 11 human Neks have been functionally assigned to one of the three core functions established for this family in mammals: (1) centrioles/mitosis; (2) primary ciliary function/ciliopathies; and (3) DNA damage response (DDR). Recent findings, especially on Nek 1 and 8, showed however, that several Neks participate in parallel in at least two of these contexts: primary ciliary function and DDR. In the core section of this in-depth review, we report the current detailed functional knowledge on each of the 11 Neks. In the discussion, we return to the cross-connections among Neks and point out how our and other groups’ functional and interactomics studies revealed that most Neks interact with protein partners associated with two if not all three of the functional contexts. We then raise the hypothesis that Neks may be the connecting regulatory elements that allow the cell to fine tune and synchronize the cellular events associated with these three core functions. The new and exciting findings on the Nek family open new perspectives and should allow the Neks to finally claim the attention they deserve in the field of kinases and cell cycle biology.
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Combined genomic expressions as a diagnostic factor for oral squamous cell carcinoma. Genomics 2014; 103:317-22. [DOI: 10.1016/j.ygeno.2013.11.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2013] [Revised: 08/05/2013] [Accepted: 11/29/2013] [Indexed: 11/19/2022]
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Bian Z, Liao H, Zhang Y, Wu Q, Zhou H, Yang Z, Fu J, Wang T, Yan L, Shen D, Li H, Tang Q. Never in mitosis gene A related kinase-6 attenuates pressure overload-induced activation of the protein kinase B pathway and cardiac hypertrophy. PLoS One 2014; 9:e96095. [PMID: 24763737 PMCID: PMC3999101 DOI: 10.1371/journal.pone.0096095] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2013] [Accepted: 04/02/2014] [Indexed: 12/31/2022] Open
Abstract
Cardiac hypertrophy appears to be a specialized form of cellular growth that involves the proliferation control and cell cycle regulation. NIMA (never in mitosis, gene A)-related kinase-6 (Nek6) is a cell cycle regulatory gene that could induce centriole duplication, and control cell proliferation and survival. However, the exact effect of Nek6 on cardiac hypertrophy has not yet been reported. In the present study, the loss- and gain-of-function experiments were performed in Nek6 gene-deficient (Nek6−/−) mice and Nek6 overexpressing H9c2 cells to clarify whether Nek6 which promotes the cell cycle also mediates cardiac hypertrophy. Cardiac hypertrophy was induced by transthoracic aorta constriction (TAC) and then evaluated by echocardiography, pathological and molecular analyses in vivo. We got novel findings that the absence of Nek6 promoted cardiac hypertrophy, fibrosis and cardiac dysfunction, which were accompanied by a significant activation of the protein kinase B (Akt) signaling in an experimental model of TAC. Consistent with this, the overexpression of Nek6 prevented hypertrophy in H9c2 cells induced by angiotonin II and inhibited Akt signaling in vitro. In conclusion, our results demonstrate that the cell cycle regulatory gene Nek6 is also a critical signaling molecule that helps prevent cardiac hypertrophy and inhibits the Akt signaling pathway.
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Affiliation(s)
- Zhouyan Bian
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P. R. China
- Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei Province, P. R. China
| | - Haihan Liao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P. R. China
- Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei Province, P. R. China
| | - Yan Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P. R. China
- Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei Province, P. R. China
| | - Qingqing Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P. R. China
- Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei Province, P. R. China
| | - Heng Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P. R. China
| | - Zheng Yang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P. R. China
- Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei Province, P. R. China
| | - Jinrong Fu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P. R. China
| | - Teng Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P. R. China
- Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei Province, P. R. China
| | - Ling Yan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P. R. China
| | - Difei Shen
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P. R. China
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P. R. China
- Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei Province, P. R. China
| | - Qizhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P. R. China
- Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei Province, P. R. China
- * E-mail:
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Discovery of novel inhibitors for Nek6 protein through homology model assisted structure based virtual screening and molecular docking approaches. ScientificWorldJournal 2014; 2014:967873. [PMID: 24587765 PMCID: PMC3920677 DOI: 10.1155/2014/967873] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 11/13/2013] [Indexed: 01/24/2023] Open
Abstract
Nek6 is a member of the NIMA (never in mitosis, gene A)-related serine/threonine kinase family that plays an important role in the initiation of mitotic cell cycle progression. This work is an attempt to emphasize the structural and functional relationship of Nek6 protein based on homology modeling and binding pocket analysis. The three-dimensional structure of Nek6 was constructed by molecular modeling studies and the best model was further assessed by PROCHECK, ProSA, and ERRAT plot in order to analyze the quality and consistency of generated model. The overall quality of computed model showed 87.4% amino acid residues under the favored region. A 3 ns molecular dynamics simulation confirmed that the structure was reliable and stable. Two lead compounds (Binding database ID: 15666, 18602) were retrieved through structure-based virtual screening and induced fit docking approaches as novel Nek6 inhibitors. Hence, we concluded that the potential compounds may act as new leads for Nek6 inhibitors designing.
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Pospelova TV, Bykova TV, Zubova SG, Katolikova NV, Yartzeva NM, Pospelov VA. Rapamycin induces pluripotent genes associated with avoidance of replicative senescence. Cell Cycle 2013; 12:3841-51. [PMID: 24296616 DOI: 10.4161/cc.27396] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Primary rodent cells undergo replicative senescence, independent from telomere shortening. We have recently shown that treatment with rapamycin during passages 3-7 suppressed replicative senescence in rat embryonic fibroblasts (REFs), which otherwise occurred by 10-14 passages. Here, we further investigated rapamycin-primed cells for an extended number of passages. Rapamycin-primed cells continued to proliferate without accumulation of senescent markers. Importantly, these cells retained the ability to undergo serum starvation- and etoposide-induced cell cycle arrest. The p53/p21 pathway was functional. This indicates that rapamycin did not cause either transformation or loss of cell cycle checkpoints. We found that rapamycin activated transcription of pluripotent genes, oct-4, sox-2, nanog, as well as further upregulated telomerase (tert) gene. The rapamycin-derived cells have mostly non-rearranged, near-normal karyotype. Still, when cultivated for a higher number of passages, these cells acquired a chromosomal marker within the chromosome 3. We conclude that suppression mTORC1 activity may prevent replicative senescence without transformation of rodent cells.
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Affiliation(s)
- Tatiana V Pospelova
- Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia; St.Petersburg State University; St. Petersburg, Russia
| | - Tatiana V Bykova
- Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia; St.Petersburg State University; St. Petersburg, Russia
| | - Svetlana G Zubova
- Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia; St.Petersburg State University; St. Petersburg, Russia
| | | | - Natalia M Yartzeva
- Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia
| | - Valery A Pospelov
- Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia; St.Petersburg State University; St. Petersburg, Russia
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Halicka HD, Zhao H, Li J, Lee YS, Hsieh TC, Wu JM, Darzynkiewicz Z. Potential anti-aging agents suppress the level of constitutive mTOR- and DNA damage- signaling. Aging (Albany NY) 2013; 4:952-65. [PMID: 23363784 PMCID: PMC3615161 DOI: 10.18632/aging.100521] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Two different mechanisms are considered to be the primary cause of aging. Cumulative DNA damage caused by reactive oxygen species (ROS), the by-products of oxidative phosphorylation, is one of these mechanisms (ROS concept). Constitutive stimulation of mitogen- and nutrient-sensing mTOR/S6 signaling is the second mechanism (TOR concept). The flow- and laser scanning- cytometric methods were developed to measure the level of the constitutive DNA damage/ROS- as well as of mTOR/S6- signaling in individual cells. Specifically, persistent activation of ATM and expression of γH2AX in untreated cells appears to report constitutive DNA damage induced by endogenous ROS. The level of phosphorylation of Ser235/236-ribosomal protein (RP), of Ser2448-mTOR and of Ser65-4EBP1, informs on constitutive signaling along the mTOR/S6 pathway. Potential gero-suppressive agents rapamycin, metformin, 2-deoxyglucose, berberine, resveratrol, vitamin D3 and aspirin, all decreased the level of constitutive DNA damage signaling as seen by the reduced expression of γH2AX in proliferating A549, TK6, WI-38 cells and in mitogenically stimulated human lymphocytes. They all also decreased the level of intracellular ROS and mitochondrial trans-membrane potential ΔΨm, the marker of mitochondrial energizing as well as reduced phosphorylation of mTOR, RP-S6 and 4EBP1. The most effective was rapamycin. Although the primary target of each on these agents may be different the data are consistent with the downstream mechanism in which the decline in mTOR/S6K signaling and translation rate is coupled with a decrease in oxidative phosphorylation, (revealed by ΔΨm) that leads to reduction of ROS and oxidative DNA damage. The decreased rate of translation induced by these agents may slow down cells hypertrophy and alleviate other features of cell aging/senescence. Reduction of oxidative DNA damage may lower predisposition to neoplastic transformation which otherwise may result from errors in repair of DNA sites coding for oncogenes or tumor suppressor genes. The data suggest that combined assessment of constitutive γH2AX expression, mitochondrial activity (ROS, ΔΨm) and mTOR signaling provides an adequate gamut of cell responses to evaluate effectiveness of gero-suppressive agents.
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Affiliation(s)
- H Dorota Halicka
- Brander Cancer Research Institute, Department of Pathology, New York Medical College, Valhalla, NY 10595, USA
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McCubrey JA, Demidenko ZN. Recent discoveries in the cycling, growing and aging of the p53 field. Aging (Albany NY) 2013; 4:887-93. [PMID: 23425920 PMCID: PMC3615156 DOI: 10.18632/aging.100529] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The P53 gene and it product p53 protein is the most studied tumor suppressor, which was considered as oncogene for two decades until 1990. More than 60 thousand papers on the topic of p53 has been abstracted in Pubmed. What yet could be discovered about its role in cell death, growth arrest and apoptosis, as well as a mediator of the therapeutic effect of anticancer drugs. Still during recent few years even more amazing discoveries have been done. Here we review such topics as suppression of epigenetic silencing of a large number of non-coding RNAs, role of p53 in suppression of the senescence phenotype, inhibition of oncogenic metabolism, protection of normal cells from chemotherapy and even tumor suppression without apoptosis and cell cycle arrest.
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Affiliation(s)
- James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, NC 27858, USA.
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The inhibition of Nek6 function sensitizes human cancer cells to premature senescence upon serum reduction or anticancer drug treatment. Cancer Lett 2013; 335:175-82. [PMID: 23416273 DOI: 10.1016/j.canlet.2013.02.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Revised: 02/01/2013] [Accepted: 02/05/2013] [Indexed: 12/30/2022]
Abstract
The induction of premature senescence in cancer cells was proposed as an effective cancer treatment strategy. In this paper, we show that the inhibition of Nek6 expression by Nek6 siRNA-mediated knockdown or the overexpression of a dominant negative form of Nek6 (Nek6KM) induced premature senescence as well as cell death under reduced serum conditions in multiple cancer cell lines, including both p53 wild-type and p53 mutant/null backgrounds. Moreover, cancer cells expressing Nek6KM exhibited significantly increased premature senescence upon treatment with the anticancer drugs doxorubicin (DOX) and camptothecin (CPT). Significantly, the overexpression of Nek6KM also inhibited tumor growth and promoted premature senescence in vivo in a xenograft mouse model. Taken together, our results further confirm that Nek6 plays an important role in the premature senescence of cancer cells, suggesting that Nek6 may be a potential therapeutic target for human cancers.
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48
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Fry AM, O'Regan L, Sabir SR, Bayliss R. Cell cycle regulation by the NEK family of protein kinases. J Cell Sci 2012; 125:4423-33. [PMID: 23132929 DOI: 10.1242/jcs.111195] [Citation(s) in RCA: 260] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Genetic screens for cell division cycle mutants in the filamentous fungus Aspergillus nidulans led to the discovery of never-in-mitosis A (NIMA), a serine/threonine kinase that is required for mitotic entry. Since that discovery, NIMA-related kinases, or NEKs, have been identified in most eukaryotes, including humans where eleven genetically distinct proteins named NEK1 to NEK11 are expressed. Although there is no evidence that human NEKs are essential for mitotic entry, it is clear that several NEK family members have important roles in cell cycle control. In particular, NEK2, NEK6, NEK7 and NEK9 contribute to the establishment of the microtubule-based mitotic spindle, whereas NEK1, NEK10 and NEK11 have been implicated in the DNA damage response. Roles for NEKs in other aspects of mitotic progression, such as chromatin condensation, nuclear envelope breakdown, spindle assembly checkpoint signalling and cytokinesis have also been proposed. Interestingly, NEK1 and NEK8 also function within cilia, the microtubule-based structures that are nucleated from basal bodies. This has led to the current hypothesis that NEKs have evolved to coordinate microtubule-dependent processes in both dividing and non-dividing cells. Here, we review the functions of the human NEKs, with particular emphasis on those family members that are involved in cell cycle control, and consider their potential as therapeutic targets in cancer.
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Affiliation(s)
- Andrew M Fry
- Department of Biochemistry, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
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49
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Panneerselvam J, Park HK, Zhang J, Dudimah FD, Zhang P, Wang H, Fei P. FAVL impairment of the Fanconi anemia pathway promotes the development of human bladder cancer. Cell Cycle 2012; 11:2947-55. [PMID: 22828653 PMCID: PMC3419064 DOI: 10.4161/cc.21400] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Effectiveness of DNA cross-linking drugs in the treatment of bladder cancer suggests that bladder cancer cells may have harbored an insufficient cellular response to DNA cross-link damage, which will sensitize cells to DNA cross-linking agents. Cell sensitivity benefits from deficient DNA damage responses, which, on the other hand, can cause cancer. Many changed cellular signaling pathways are known to be involved in bladder tumorigenesis; however, DNA cross-link damage response pathway [Fanconi anemia (FA) pathway], whose alterations appear to be a plausible cause of the development of bladder cancer, remains an under-investigated area in bladder cancer research. In this study, we found FAVL (variant of FA protein L--FANCL) was elevated substantially in bladder cancer tissues examined. Ectopic expression of FAVL in bladder cancer cells as well as normal human cells confer an impaired FA pathway and hypersensitivity to Mitomycin C, similar to those found in FA cells, indicating that FAVL elevation may possess the same tumor promotion potential as an impaired FA pathway harbored in FA cells. Indeed, a higher level of FAVL expression can promote the growth of bladder cancer cells in vitro and in vivo, which, at least partly, results from FAVL perturbation of FANCL expression, an essential factor for the activation of the FA pathway. Moreover, a higher level of FAVL expression was found to be associated with chromosomal instability and the invasiveness of bladder cancer cells. Collectively, FAVL elevation can increase the tumorigenic potential of bladder cancer cells, including the invasive potential that confers the development of advanced bladder cancer. These results enhance our understanding the pathogenesis of human bladder cancer, holding a promise to develop additional effective tools to fight human bladder cancer.
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Affiliation(s)
| | - Hwan Ki Park
- Department of Laboratory Medicine and Pathology; Mayo Clinic; Rochester, MN USA
| | - Jun Zhang
- Department of Laboratory Medicine and Pathology; Mayo Clinic; Rochester, MN USA
| | | | - Piyan Zhang
- Department of Laboratory Medicine and Pathology; Mayo Clinic; Rochester, MN USA
| | - Hong Wang
- Department of Laboratory Medicine and Pathology; Mayo Clinic; Rochester, MN USA
| | - Peiwen Fei
- University of Hawaii Cancer Center; University of Hawaii; Honolulu, HI USA
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Kasap E, Boyacioglu SÖ, Korkmaz M, Yuksel ES, Unsal B, Kahraman E, Ozütemiz O, Yuceyar H. Aurora kinase A (AURKA) and never in mitosis gene A-related kinase 6 (NEK6) genes are upregulated in erosive esophagitis and esophageal adenocarcinoma. Exp Ther Med 2012; 4:33-42. [PMID: 23060919 DOI: 10.3892/etm.2012.561] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Accepted: 04/19/2012] [Indexed: 02/07/2023] Open
Abstract
Gastroesophageal reflux disease is a risk factor for esophageal adenocarcinoma yet studies that have investigated the relationship between erosive esophagitis and esophageal adenocarcinoma have usually focused on symptom-related evidence or polymorphisms. There are no epigenetic gene expression studies on this topic. In this study, we aimed to evaluate the relationship between erosive esophagitis and esophageal adenocarcinoma to identify whether there is a genetic predisposition for esophageal adenocarcinoma. The Human Epigenetic Chromatin Modification Enzyme RT(2) Profiler(™) PCR array (PAHS-085A) was used to detect the expression of 84 key genes encoding enzymes. This was carried out prospectively for samples from 60 patients (20 patients as a control group, 20 patients with erosive esophagitis and 20 patients with esophageal adenocarcinoma). AURKA, AURKB, NEK6 were expressed at significantly higher levels in esophageal adenocarcinoma compared to the control group. MBD2 was expressed at significantly lower levels in the esophageal adenocarcinoma group compared to the control group. AURKA, AURKC, HDAC9 and NEK6 were expressed at significantly higher levels in erosive esophagitis compared to the control group. There was no difference in upregulated gene expression between the erosive esophagitis and esophageal adenocarcinoma. MBD2 was significantly downregulated in esophageal adenocarcinoma compared to erosive esophagitis. NEK6 and AURKA were significantly upregulated in esophageal adenocarcinoma and erosive esophagitis compared to the control group. This is a novel study on the genetic predisposition for erosive esophagitis and esophageal adenocarcinoma. AURKA and NEK6 are two promising genetic markers for erosive esophagitis and esophageal adenocarcinoma.
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