Silencing of IKKε using siRNA inhibits proliferation and invasion of glioma cells in vitro and in vivo
Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, PR China. International Journal of Oncology
(Impact Factor: 3.03).
04/2012; 41(1):169-78. DOI: 10.3892/ijo.2012.1452
Recent studies implicated IKKε in the pathogenesis of many human cancers by promoting cell proliferation, increasing tumor angiogenesis and metastasis, and generating resistance to cell apoptosis. However, whether IKKε can influence the invasive ability and proliferation of glioma cells remains largely unknown. In this study, we showed that overexpression of IKKε is positively correlated to glioma pathological grade, suggesting that IKKε plays a role in tumor progression, rather than tumor initiation. Targeted knockdown of IKKε in human glioma cells using siRNA, was associated with inhibition of cell growth, cell cycle arrest and decreased cell invasion; however, notable apoptosis was not observed. Furthermore, we demonstrated that transposition of NF-κB p65 resulted in the alteration of these phenotypes. Tumor growth was attenuated in established subcutaneous gliomas in nude mice treated with IKKε siRNA in vivo. Collectively, our results suggest that deregulation of IKKε plays a pivotal role in the uncontrolled proliferation and malignant invasion of glioma cells in vitro and in vivo by targeting NF-κB. Silencing of IKKε using synthetic siRNAs may offer a novel therapeutic strategy for the treatment of glioma.
Available from: David Bauer
- "Further, the correlation of IKKe with cell proliferation and transformation, has given rise to its being classified as oncogene . Silencing or inhibition of IKKe results in inhibition of cell growth, proliferation, invasion , clonogenicity, migration  and overcoming its contributory Table 2 Function categories affected by TNF-alpha vs control. "
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ABSTRACT: TNFα receptors are constitutively overexpressed in tumor cells, correlating to sustain elevated NFκB and monocyte chemotactic protein-1 (MCP-1/CCL2) expression. The elevation of CCL2 evokes aggressive forms of malignant tumors marked by tumor associated macrophage (TAM) recruitment, cell proliferation, invasion and angiogenesis. Previously, we have shown that the organo-sulfur compound diallyl disulfide (DADS) found in garlic (Allium sativum) attenuates TNFα induced CCL2 production in MDA-MB-231 cells. In the current study, we explored the signaling pathways responsible for DADS suppressive effect on TNFα mediated CCL2 release using PCR Arrays, RT-PCR and western blots. The data in this study show that TNFα initiates a rise in NFκB mRNA, which is not reversed by DADS. However, TNFα induced heightened expression of IKKε and phosphorylated ERK. The expression of these proteins corresponds to increased CCL2 release that can be attenuated by DADS. CCL2 induction by TNFα was also lessened by inhibitors of p38 (SB202190) and MEK (U0126) but not JNK (SP 600125), all of which were suppressed by DADS. In conclusion, the obtained results indicate that DADS down regulates TNFα invoked CCL2 production primarily through reduction of IKKε and phosphorylated-ERK, thereby impairing MAPK/ERK, and NFκB pathway signaling. Future research will be required to evaluate the effects of DADS on the function and expression of TNFα surface receptors.
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Cytokine 06/2015; 75(1). DOI:10.1016/j.cyto.2014.12.007 · 2.66 Impact Factor
Available from: Julia Stellzig
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ABSTRACT: Signal transmission by the noncanonical IkappaB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IKKε, requires interaction with adapter proteins such as TRAF associated NF-κB activator (TANK). Although increased expression or dysregulation of both kinases has been described for a variety of human cancers, this study shows that deregulated expression of the TANK protein is frequently occurring in glioblastomas (GBMs). The functional relevance of TANK was analyzed in a panel of GBM-derived cell lines and revealed that knockdown of TANK arrests cells in the S-phase and prohibits tumor cell migration. Deregulated TANK expression affects several signaling pathways controlling cell proliferation and the inflammatory response. Interference with stoichiometrically assembled signaling complexes by overexpression or silencing of TANK prevented constitutive interferon-regulatory factor 3 (IRF3) phosphorylation. Knockdown of TANK frequently prevents constitutive activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). TANK-mediated ERK1/2 activation is independent from the canonical MAP kinase or ERK kinase (MEK) 1/2-mediated pathway and utilizes an alternative pathway that uses a TBK1/IKKε/Akt signaling axis, thus identifying a novel pathway suitable to block constitutive ERK1/2 activity.
Oncogenesis 11/2013; 2(e79). DOI:10.1038/oncsis.2013.42 · 3.95 Impact Factor
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ABSTRACT: Glioblastoma (GBM) is an aggressive and incurable brain tumor with a grave prognosis. Recurrence is inevitable even with maximal surgical resection, in large part because GBM is a highly invasive tumor. Invasiveness also contributes to the failure of multiple cornerstones of GBM therapy, including radiotherapy, temozolomide chemotherapy, and vascular endothelial growth factor blockade. In recent years there has been significant progress in the identification of protein biomarkers of invasive phenotype in GBM. In this article, we comprehensively review the literature and survey a broad spectrum of biomarkers, including proteolytic enzymes, extracellular matrix proteins, cell adhesion molecules, neurodevelopmental factors, cell signaling and transcription factors, angiogenic effectors, metabolic proteins, membrane channels, and cytokines and chemokines. In light of the marked variation seen in outcomes in GBM patients, the systematic use of these biomarkers could be used to form a framework for better prediction, prognostication, and treatment selection, as well as the identification of molecular targets for further laboratory investigation and development of nascent, directed therapies.
Molecular Neurobiology 11/2013; 49(3). DOI:10.1007/s12035-013-8593-5 · 5.14 Impact Factor
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