scholarly journals Effects of Aurora kinase A on mouse decidualization via Stat3-plk1-cdk1 pathway

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Peng-Chao Wang ◽  
Si-Ting Chen ◽  
Zeng-Ming Yang
Keyword(s):  
Signaling Pathway ◽  
Aurora Kinase ◽  
Aurora A ◽  
Aurora Kinase A ◽  
Protein Levels ◽  
Decidual Cells ◽  
Implantation Sites ◽  
Kinase A

Abstract Background Decidualization is essential to the successful pregnancy in mice. The molecular mechanisms and effects of Aurora kinase A (Aurora A) remain poorly understood during pregnancy. This study is the first to investigate the expression and role of Aurora A during mouse decidualization. Methods Quantitative real time polymerase chain reaction, western blotting and in situ hybridization were used to determine the expression of Aurora A in mouse uteri. Aurora A activity was inhibited by Aurora A inhibitor to explore the role of Aurora A on decidualization via regulating the Aurora A/Stat3/Plk1/Cdk1 signaling pathway. Results Aurora A was strongly expressed at implantation sites compared with inter-implantation sites. Furthermore, Aurora A was also significantly increased in oil-induced deciduoma compared with control. Both Aurora A mRNA and protein were significantly increased under in vitro decidualization. Under in vitro decidualization, Prl8a2, a marker of mouse decidualization, was significantly decreased by TC-S 7010, an Aurora A inhibitor. Additionally, Prl8a2 was reduced by Stat3 inhibitor, Plk1 inhibitor and Cdk1 inhibitor, respectively. Moreover, the protein levels of p-Stat3, p-Plk1 and p-Cdk1 were suppressed by TC-S 7010. The protein levels of p-Stat3, p-Plk1 and p-Cdk1 were also suppressed by S3I-201, a Stat3 inhibitor). SBE 13 HCl (Plk1 inhibitor) could reduce the protein levels of p-Plk1 and p-Cdk1. Collectively, Aurora A could regulate Stat3/Plk1/Cdk1 signaling pathway. Conclusion Our study shows that Aurora A is expressed in decidual cells and should be important for mouse decidualization. Aurora A/Stat3/Plk1/Cdk1 signaling pathway may be involved in mouse decidualization.

Role of aurora kinase A on regulating inflammation and inducing NF-κB pathway activation in gastric cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 78-78
Author(s):  
Ahmed M. Katsha ◽  
Vikas Sehdev ◽  
Mohammed Soutto ◽  
DunFa Peng ◽  
Abbes Belkhiri ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Target Genes ◽  
Aurora Kinase ◽  
Luciferase Reporter ◽  
Human Gastric Cancer ◽  
Nuclear Staining ◽  
Aurora Kinase A ◽  
Kinase A

78 Background: Aurora kinase A gene (AURKA) is frequently amplified and/or overexpressed in several malignancies. Inflammation contributes to the pathogenesis of gastric tumorigenesis. We explored the roles of AURKA in inflammation and tumorigenesis. Methods: Immunofluorescence, immunohistochemistry, Quantitative real-time PCR, immunoblot, co-immunoprecipitation, luciferase reporter, and in vitro kinase assays were used to analyze AGS and MKN28 gastric cancer cells. We also analyzed Tff1–/– mice, growth of tumor xenografts, and human tissues. Results: We showed an elevated level of AURKA in the Tff1–/– gastric tissues as compared to wild-type. We also found a positive correlation between AURKA and inflammation (coefficient r = 0.25; P = 0.0056) as well as TNF-α (coefficient r = 0.25; P = 0.0057). AURKA inhibition by MLN8237, a specific AURKA inhibitor, reduced nuclear staining of NFκB in human gastric cancer samples and mouse epithelial cells, suppressed NFκB reporter activity, and reduced the expression of NFκB target genes that regulate inflammation and cell survival. Additionally, AURKA inhibition reduced xenograft tumor size in mice and reversed the development of gastric tumors in Tff1–/– mice. Further, we found that AURKA regulate NFκB activity by directly binding and phosphorylating IκBα in vitro. Premalignant and malignant lesions from the gastric mucuosa of patients had increased levels of AURKA protein and nuclear NFκB, compared with healthy gastric tissue. Conclusions: In analyses of gastric cancer cell lines, human tissue samples, and mouse models, we found AURKA to be upregulated during chronic inflammation to promote IκBα-mediated activation of NFκB and tumorigenesis. This provides a novel role of AURKA in cancer and shows the importance of targeting it as a therapeutic approach in cancer treatment.

scholarly journals ISL1 promoted tumorigenesis and EMT via Aurora kinase A-induced activation of PI3K/AKT signaling pathway in neuroblastoma

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Mengzhen Li ◽  
Chengtao Sun ◽  
Xiaoyun Bu ◽  
Yi Que ◽  
Lian Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Malignant Tumors ◽  
Aurora Kinase ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Aurora Kinase A ◽  
Kinase A

AbstractNeuroblastoma (NB) is the most common extracranial solid malignancy in children and its mortality rate is relatively high. However, driver genes of NB are not clearly identified. Using bioinformatics analysis, we determined the top 8 differentially expressed genes (DEGs) in NB, including GFAP, PAX6, FOXG1, GAD1, PTPRC, ISL1, GRM5, and GATA3. Insulin gene enhancer binding protein 1 (ISL1) is a LIM homeodomain transcription factor which has been found to be highly expressed in a variety of malignant tumors, but the function of ISL1 in NB has not been fully elucidated. We identified ISL1 as an oncogene in NB. ISL1 is preferentially upregulated in NB tissues compared with normal tissues. High ISL1 expression is significantly associated with poor outcome of NB patients. Knockdown of ISL1 markedly represses proliferation and induces cell apoptosis in vitro, and suppresses tumorigenicity in vivo, while overexpression of ISL1 has the opposite effects. Mechanistically, we demonstrate that ISL1 promotes cell proliferation and EMT transformation through PI3K/AKT signaling pathway by upregulating Aurora kinase A (AURKA), a serine-threonine kinase that is essential for the survival of NB cells. The blockade of AURKA attenuates the function of ISL1 overexpression in the regulation of cell proliferation and migration, Conclusively, this study showed that ISL1 targeted AURKA to facilitate the development of NB, which provided new insights into the tumorigenesis of NB. Thus, ISL1 may be a promising therapeutic target in the future.

scholarly journals Aurora Kinase A as a Diagnostic and Prognostic Marker of Malignant Mesothelioma

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhenying Guo ◽  
Li Shen ◽  
Ningning Li ◽  
Xiaoxiao Wu ◽  
Canming Wang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Prognostic Marker ◽  
Malignant Mesothelioma ◽  
Prognostic Markers ◽  
Kegg Pathway ◽  
Aurora Kinase ◽  
Aurora A ◽  
Hub Genes ◽  
Aurora Kinase A ◽  
Kinase A

BackgroundMalignant mesothelioma (MM) is a highly aggressive cancer with a poor prognosis. Despite the use of several well-known markers, the diagnosis of MM is still challenging in some cases. we applied bioinformatics to identify key genes and screen for diagnostic and prognostic markers of MM.MethodsThe expression profiles of GSE2549 and GSE112154 microarray datasets from the Gene Expression Omnibus database contained 87 cases of MM tissue and 8 cases of normal mesothelial tissue in total. The GEO2R tool was used to detect differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs were performed using DAVID Bioinformatics Resources. The DEGs protein-protein interaction networks were constructed from the STRING database. Cytoscape was used to identify significant modules and hub genes. The GEPIA database was used to explore relationships between hub genes and prognosis of MM. Immunohistochemistry was used to analyze protein expression in tissue microarrays with 47 Chinese MM tissues. Statistical analyses diagnostic and prognostic values.Results346 DEGs were identified: 111 genes upregulated, and 235 downregulated. GO analysis showed that the primary biological processes of these DEGs were cell adhesion, leukocyte migration, and angiogenesis. The main cellular components included the extracellular space, extracellular exosome, and extracellular region. The molecular functions were integrin binding, heparin binding, and calcium ion binding. KEGG pathway analysis showed that DEGs are primarily involved in PPAR signaling pathway, extracellular matrix–receptor interactions, and regulation of lipolysis in adipocytes. Survival analysis showed that seven genes—AURKA, GAPDH, TOP2A, PPARG, SCD, FABP4, and CEBPA—may be potential prognostic markers for MM. Immunohistochemical studies showed that Aurora kinase A (AURKA gene encode, Aurora-A) and GAPDH were highly expressed in MM tissue in comparison with normal mesothelial tissue. Kaplan-Meier analysis confirmed a correlation between Aurora-A protein expression and overall survival but did not confirm a correlation with GAPDH. The receiver operating characteristic curves of Aurora-A protein expression suggested acceptable accuracy (AUC = 0.827; 95% CI [0.6686 to 0.9535]; p = 0.04). The sensitivity and specificity of Aurora-A were 83.33% and 77.78%, respectively.ConclusionAurora-A could be an optimal diagnostic biomarker and a potential prognostic marker for MM.

scholarly journals Mechanisms for nonmitotic activation of Aurora-A at cilia

2017 ◽  
Vol 45 (1) ◽  
pp. 37-49 ◽  
Author(s):  
Vladislav Korobeynikov ◽  
Alexander Y. Deneka ◽  
Erica A. Golemis
Keyword(s):  
Cell Surface ◽  
Primary Cilium ◽  
Mitotic Spindle ◽  
Biological Function ◽  
Aurora Kinase ◽  
Aurora Kinase A ◽  
The Past ◽  
A Current ◽  
Kinase A

Overexpression of the Aurora kinase A (AURKA) is oncogenic in many tumors. Many studies of AURKA have focused on activities of this kinase in mitosis, and elucidated the mechanisms by which AURKA activity is induced at the G2/M boundary through interactions with proteins such as TPX2 and NEDD9. These studies have informed the development of small molecule inhibitors of AURKA, of which a number are currently under preclinical and clinical assessment. While the first activities defined for AURKA were its control of centrosomal maturation and organization of the mitotic spindle, an increasing number of studies over the past decade have recognized a separate biological function of AURKA, in controlling disassembly of the primary cilium, a small organelle protruding from the cell surface that serves as a signaling platform. Importantly, these activities require activation of AURKA in early G1, and the mechanisms of activation are much less well defined than those in mitosis. A better understanding of the control of AURKA activity and the role of AURKA at cilia are both important in optimizing the efficacy and interpreting potential downstream consequences of AURKA inhibitors in the clinic. We here provide a current overview of proteins and mechanisms that have been defined as activating AURKA in G1, based on the study of ciliary disassembly.

scholarly journals CEP215 and AURKA regulate spindle pole focusing and aMTOC organization in mouse oocytes

Reproduction ◽  
2020 ◽  
Vol 159 (3) ◽  
pp. 261-274
Author(s):  
Xiaotian Wang ◽  
Claudia Baumann ◽  
Rabindranath De La Fuente ◽  
Maria M Viveiros
Keyword(s):  
Critical Role ◽  
Super Resolution ◽  
Aurora Kinase ◽  
Spindle Pole ◽  
Meiotic Spindle ◽  
Dependent Manner ◽  
Aurora Kinase A ◽  
Mouse Oocytes ◽  
Kinase A

Acentriolar microtubule-organizing centers (aMTOCs) play a critical role in stable meiotic spindle assembly in oocytes, necessary for accurate chromosome segregation. Yet, there is a limited understanding of the essential regulatory components of these unique MTOCs. In somatic cells, CEP215 (Centrosomal Protein 215) serves as an important regulator of centrosome maturation and spindle organization. Here, we assessed whether it has a similar function in mouse oocytes. CEP215 was detected in oocyte lysates and specifically localized to aMTOCs throughout the progression of meiosis in a pericentrin-dependent manner. Super-resolution microscopy revealed CEP215 co-localization with pericentrin and a unique pore/ring-like structural organization of aMTOCs. Interestingly, inhibition of Aurora Kinase A in either MI or MII-stage oocytes resulted in a striking loss of the ring-like aMTOC organization and pronounced CEP215 clustering at spindle poles, as well as shorter spindles with highly focused poles. In vitro siRNA-mediated transcript knockdown effectively reduced CEP215 in approximately 85% of the oocytes. Maturation rates to MII were similar in the Cep215 siRNA and injected controls; however, a high percentage (~40%) of the Cep215-knockdown oocytes showed notable variations in spindle pole focusing. Surprisingly, pericentrin and γ-tubulin localization and fluorescence intensity at aMTOCs were unaltered in knockdown oocytes, contrasting with mitotic cells where CEP215 depletion reduced γ-tubulin at centrosomes. Our results demonstrate that CEP215 is a functional component of oocyte aMTOCs and participates in the regulation of meiotic spindle pole focusing. Moreover, these studies reveal a vital role for Aurora Kinase A activity in the maintenance of aMTOC organization in oocytes.

Combination Therapy with the Histone Deacetylase Inhibitor Vorinostat Plus the Novel Aurora Kinase A Inhibitor MK-5108 Leads to Enhanced Lymphoma Cell Death Due to Acetylation of p53 and Repression of c-Myc, hTERT, and miRNA Levels.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1690-1690
Author(s):  
Leo Kretzner ◽  
Anna Scuto ◽  
Kowolik Claudia ◽  
Richard Jove ◽  
Stephen J Forman ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Growth ◽  
Research Funding ◽  
Aurora Kinase ◽  
Aurora Kinase A ◽  
Non Hodgkin Lymphoma ◽  
Deacetylase Inhibitor ◽  
Kinase A

Abstract Abstract 1690 Poster Board I-716 Background Patients with relapsed or refractory Hodgkin (HL) and Non Hodgkin Lymphoma (NHL) have few options after salvage therapy and transplant, and new agents are thus needed. MK-5108 is a novel aurora kinase inhibitor (AKI) with specificity against aurora kinase A, that produces G2/M phase cell cycle arrest. We show that addition of vorinostat, a histone and protein deacetylase inhibitor, to AKI treatment results in reactivation of proapoptotic genes and enhanced lymphoma cell death. A panel of HL and NHL cell lines was studied with either drug or the combination, using cell growth, apoptosis, and flow cytometry assays, followed by molecular studies. Results MK-5108 alone at 0.1 – 3 mM results in significant growth inhibition and apoptosis in multiple cell lines representing Hodgkin, Burkitt, and Non-Hodgkin lymphoma types, interestingly,DHL-4 and DHL-6 cells were more sensitive to this agent than to the pan-AKI MK-0457. Vorinostat alone at a dose range of 0.5 – 3 mM reduces cell growth by 50% or more in all lines tested. The combination of 1.5 mM vorinostat and 100 nM MK-5108 results in over 85% apoptosis of multiple lymphoma lines tested at 72 hours. Cell cycle analyses by FACS of MK-5108 treated cells show an increased percentage of cells in G2/M with few cells in sub-G1, whereas in combination with vorinostat the G2/M peak decreases and there is a significant increase in the apoptotic sub-G1 population. Real-time PCR analysis and immunoblotting of L540 cells treated with either single agent or in combination revealed that vorinostat treatment leads to alteration in pro-apoptosis, growth arrest, and DNA damage response genes. Myc mRNA and protein levels are reduced by vorinostat, and repression of microRNAs (miRNAs) in the Myc-regulated polycistronic cluster of miRNAs of chromosome 13, such as miR-17.5p, -17.3p, and 18, occurs with vorinostat and TSA. Prosurvival genes such as bcl-XL and hTERT are downregulated five-fold by vorinostat treatment, while the proapoptotic BAK gene is upregulated 1.5 – 2-fold. Vorinostat treatment leads to enhanced acetylation of p53, with a corresponding increase in the p53 target genes p21 and Noxa. To analyze the role of Myc inhibition in the sensitization by vorinostat of lymphoma cells to MK-5108, siRNA-mediated knock-down of Myc expression in L540 cells was performed. The siRNA-Myc transfected L540 cells showed enhanced sensitivity to MK-5108 as compared to control siRNA-null cells, as well as decreased hTERT levels, confirming the role of Myc inhibition by vorinostat as an integral part of the sensitization of lymphoma cells to MK-5108. Conclusions The HDACi vorinostat leads to both transcriptional and post-transcriptional changes that create a pro-apoptotic milieu, sensitizing the cell to centrosome-acting agents such as the aurora kinase A inhibitor MK-5108. These preclinical data support clinical trials of MK-5108 plus vorinostat in patients with relapsed or refractory lymphomas. [We acknowledge Merck Inc for providing Vorinostat, MK-0457, MK-5108, and research support.] Disclosures Kretzner: Merck: Research Funding. Yen:Merck: Research Funding. Kirschbaum:Merck: Research Funding, Speakers Bureau.

scholarly journals OTUD6A Is an Aurora Kinase A-Specific Deubiquitinase

2021 ◽  
Vol 22 (4) ◽  
pp. 1936
Author(s):  
Hyo Jin Kim ◽  
Jongchan Kim
Keyword(s):  
Therapeutic Target ◽  
Aurora Kinase ◽  
Regulatory Subunit ◽  
Aurora A ◽  
Aurora Kinases ◽  
Aurora Kinase A ◽  
Cyclin Dependent Kinases ◽  
Human Cancers ◽  
Potential Cancer ◽  
Kinase A

Aurora kinases are serine/threonine kinases required for cell proliferation and are overexpressed in many human cancers. Targeting Aurora kinases has been a therapeutic strategy in cancer treatment. Here, we attempted to identify a deubiquitinase (DUB) that regulates Aurora kinase A (Aurora-A) protein stability and/or kinase activity as a potential cancer therapeutic target. Through pull-down assays with the human DUB library, we identified OTUD6A as an Aurora-A-specific DUB. OTUD6A interacts with Aurora-A through OTU and kinase domains, respectively, and deubiquitinates Aurora-A. Notably, OTUD6A promotes the protein half-life of Aurora-A and activates Aurora-A by increasing phosphorylation at threonine 288 of Aurora-A. From qPCR screening, we identified and validated that the cancer gene CKS2 encoding Cyclin-dependent kinases regulatory subunit 2 is the most upregulated cell cycle regulator when OTUD6A is overexpressed. The results suggest that OTUD6A may serve as a therapeutic target in human cancers.

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