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Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation.

ABSTRACT: Aurora A and JAK2 kinases are involved in cell division and tumor cell survival, respectively. Here we demonstrate that ectopic expression of Aurora A and JAK2 together is more effective than each alone at inducing non-transformed cells to grow in an anchorage-independent manner and to invade. Furthermore, siRNA silencing or pharmacological inhibition of Aurora A and JAK2 with Alisertib and Ruxolitinib, respectively, is more effective than blocking each kinase alone at suppressing anchorage-dependent and -independent growth and invasion as well as at inducing apoptosis. Importantly, we have developed dual Aurora and JAK inhibitors, AJI-214 and AJI-100, which potently inhibit Aurora A, Aurora B and JAK2 in vitro. In human cancer cells, these dual inhibitors block the auto-phosphorylation of Aurora A (Thr-288) and the phosphorylation of the Aurora B substrate histone H3 (Ser-10) and the JAK2 substrate STAT3 (Tyr-705). Furthermore, AJI-214 and AJI-100 inhibit anchorage dependent and independent cell growth and invasion and induce G2/M cell cycle accumulation and apoptosis. Finally, AJI-100 caused regression of human tumor xenografts in mice. Taken together, our genetic and pharmacological studies indicate that targeting Aurora A and JAK2 together is a more effective approach than each kinase alone at inhibiting malignant transformation and warrant further advanced pre clinical investigations of dual Aurora A/JAK2 inhibitors as potential anti tumor agents.

SUBMITTER: Yang H

PROVIDER: S-EPMC4102782 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation.

Yang Hua H Lawrence Harshani R HR Kazi Aslamuzzaman A Gevariya Harsukh H Patel Ronil R Luo Yunting Y Rix Uwe U Schonbrunn Ernst E Lawrence Nicholas J NJ Sebti Said M SM

Oncotarget 20140501 10

Aurora A and JAK2 kinases are involved in cell division and tumor cell survival, respectively. Here we demonstrate that ectopic expression of Aurora A and JAK2 together is more effective than each alone at inducing non-transformed cells to grow in an anchorage-independent manner and to invade. Furthermore, siRNA silencing or pharmacological inhibition of Aurora A and JAK2 with Alisertib and Ruxolitinib, respectively, is more effective than blocking each kinase alone at suppressing anchorage-depe ...[more]

PMID: 24930769

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Project description: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.

Project description:As a crucial transcription factor, sex?determining region Y box 12 (SOX12) is closely related with tumorigenesis and malignant transformation in various malignant tumor types. To date, the specific function of SOX12 in esophageal squamous cell carcinoma (ESCC) has remained largely elusive and requires further investigation. The present study aimed to determine whether aberrant expression of SOX12 is associated with malignant development of ESCC. The expression level of SOX12 in ESCC cells and tissues was analyzed by RT?qPCR and western blotting. Short hairpin RNA (shRNA) targeting SOX12 was transfected into ESCC cells to knock down the expression of SOX12. Colony formation and Transwell assays were used to detect viability and mobility of ESCC cells. Signaling pathway?related proteins were assessed using western blot analysis and cellular immunofluorescence. Clinical prognosis data was analyzed by Kaplan?Meier and Cox logistic regression. The present results revealed that SOX12 was overexpressed in ESCC cells and tissues. Knockdown of the expression of SOX12 by shRNA inhibited the colony forming efficiency, migration and invasion capacities of ESCC cells in vitro. Recombinant protein of SOX12 could restore the aggressive phenotype of ESCC cells. Furthermore, knockdown of the expression of SOX12 inhibited the activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway by decreasing the expression of the JAK2/STAT3 signaling pathway. Recombinant protein of SOX12 could recover the activation of the JAK2/STAT3 signaling pathway. Analysis of the clinical data revealed that overexpression of SOX12 indicated shorter overall survival time (OS; P=0.0341) and disease?free survival time (DFS; P=0.04). Univariate and multivariate analysis revealed that overexpression of SOX12 was an independent factor for ESCC. In conclusion, SOX12 was revealed to serve a crucial function in sustaining the viability, as well as enhancing the motility of ESCC cells via activating the JAK2/STAT3 signaling pathway. Thus, SOX12 may potentially serve as a novel biomarker and candidate for the targeted treatment of ESCC.

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Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation.

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Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation.

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