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See detailNf- Kappa B and Chemoresistance: Could Nf- Kappa B Be an Antitumor Target?
Bentires-Alj, Mohamed; Merville, Marie-Paule ULg; Bours, Vincent ULg

in Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy (1999), 2(4), 274-276

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See detailNF-kappa B activation by double-strand breaks
Habraken, Yvette ULg; Piette, Jacques ULg

in Biochemical Pharmacology (2006), 72(9), 1132-1141

Cellular response to DNA damage is complex and relies on the simultaneous activation of different networks. It involves DNA damage recognition, repair, and induction of signalling cascades leading to cell ... [more ▼]

Cellular response to DNA damage is complex and relies on the simultaneous activation of different networks. It involves DNA damage recognition, repair, and induction of signalling cascades leading to cell cycle checkpoint activation, apoptosis, and stress related responses. The fate of damaged cells depends on the balance between pro- and antiapoptotic signals. in this decisive life or death choice, the transcription factor NF-kappa B has emerged as a prosurvival actor in most cell types. As corollary, it appears to be associated with tumorigenic process and resistance to therapeutic strategies as it protects cancerous cells from death. in this review, we will focus on NF-kappa B activation by double-strand breaks inducing agents, such as ionizing radiation and DNA topoisomerase I and II inhibitors routinely used in cancer therapy. Coinciding with the 20th anniversary of the NF-kappa B discovery, major steps of the DSB-triggered cascade have been recently identified. Two parallel cascades are necessary for NF-kappa B activation. The first one depends on ATM (activated by double-strand breaks) and the second on PIDD (activated by an unknown stress signal). The phosphorylation of NEMO by ATM is the point of convergence of these two cascades. The identification of ATM/NEMO complex as the long searched "nuclear to cytoplasm" signal leading to IKK activation is also a major piece of the puzzle. The knowledge of the precise steps leading to DSB-initiated NF kappa B activation will allow the development of specific blocking compounds reducing its prosurvival function. (c) 2006 Elsevier Inc. All rights reserved. [less ▲]

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See detailNF-kappa B activation by reactive oxygen species: Fifteen years later
Gloire, Geoffrey ULg; Legrand-Poels, Sylvie ULg; Piette, Jacques ULg

in Biochemical Pharmacology (2006), 72(11), 1493-1505

The transcription factor NF-kappa B plays a major role in coordinating innate and adaptative immunity, cellular proliferation, apoptosis and development. Since the discovery in 1991 that NF-kappa B maybe ... [more ▼]

The transcription factor NF-kappa B plays a major role in coordinating innate and adaptative immunity, cellular proliferation, apoptosis and development. Since the discovery in 1991 that NF-kappa B maybe activated by H(2)o(2), several laboratories have put a considerable effort into dissecting the molecular mechanisms underlying this activation. Whereas early studies revealed an atypical mechanism of activation, leading to I kappa B alpha Y42 phosphorylation independently Of I kappa B kinase (IKK), recent findings suggest that H2O2 activates NF-kappa B mainly through the classical IKK-dependent pathway. The molecular mechanisms leading to IKK activation are, however, cell-type specific and will be presented here. In this review, we also describe the effect of other ROS (HOCl and O-1(2)) and reactive nitrogen species on NF-kappa B activation. Finally, we critically review the recent data highlighting the role of ROS in NF-kappa B activation by proinflammatory cytokines (TNF-alpha and IL-1 beta) and lipopolysaccharide (LPS), two major components of innate immunity. (c) 2006 Elsevier Inc. All rights reserved. [less ▲]

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See detailThe Nf-Kappa B Transcription Factor and Cancer: High Expression of Nf-Kappa B- and I Kappa B-Related Proteins in Tumor Cell Lines
Bours, Vincent ULg; Dejardin, Emmanuel ULg; Goujon-Letawe, F. et al

in Biochemical Pharmacology (1994), 47(1), 145-9

NF-kappa B is a pleiotropic transcription factor which controls the expression of many genes and viruses. To date, there is good evidence, but no definitive proof, for its role in tumor formation and ... [more ▼]

NF-kappa B is a pleiotropic transcription factor which controls the expression of many genes and viruses. To date, there is good evidence, but no definitive proof, for its role in tumor formation and development of metastasis. To investigate the possibility that members of the NF-kappa B family could participate in the molecular control of the transformed and invasive phenotype, we examined the expression of these proteins in a variety of human tumor cell lines. The expression of p50, p65, p52 and I kappa B was quantified at the protein level using western immunoblot and mobility shift assay and at the RNA level by northern blot. We observed high expression of the NF-kappa B inhibitor I kappa B in the ovarian carcinoma cell line OVCAR-3 together with constitutive nuclear NF-kappa B activity. We also studied the colon carcinoma cell line HT-29 and its metastatic counterpart HTM-29 and we observed specific expression of the p52 NF-kappa B-related protein in the metastatic cells. Our data confirm that NF-kappa B could be involved in the genesis of a variety of cancers including solid tumors and provide us with interesting models to explore the exact role of these transcription factors in cancer. [less ▲]

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See detailNF-kappa B2/p100 induces Bcl-2 expression
Viatour, Patrick ULg; Bentires-Alj, Mohamed; Chariot, Alain ULg et al

in Leukemia (2003), 17(7), 1349-1356

The NF-kappaB2/p100 and bcl-3 genes are involved in chromosomal translocations described in chronic lymphocytic leukemias (CLL) and non-Hodgkin's lymphomas, and nuclear factor kappaB (NF-kappaB) protects ... [more ▼]

The NF-kappaB2/p100 and bcl-3 genes are involved in chromosomal translocations described in chronic lymphocytic leukemias (CLL) and non-Hodgkin's lymphomas, and nuclear factor kappaB (NF-kappaB) protects cancer cells against apoptosis. Therefore, we investigated whether this transcription factor could modulate the expression of the Bcl-2 antiapoptotic protein. Bcl-2 promoter analysis showed multiple putative NF-kappaB binding sites. Transfection assays of bcl-2 promoter constructs in HCT116 cells showed that NF-kappaB can indeed transactivate bcl-2. We identified a kappaB site located at position -180 that can only be bound and transactivated by p50 or p52 homodimers. As p50 and p52 homodimers are devoid of any transactivating domains, we showed that they can transactivate the bcl-2 promoter through association with Bcl-3. We also observed that stable overexpression of p100 and its processed product p52 can induce endogenous Bcl-2 expression in MCF7AZ breast cancer cells. Finally, we demonstrated that, in breast cancer and leukemic cells ( CLL), high NF-kappaB2/p100 expression was associated with high Bcl-2 expression. Our data suggest that Bcl-2 could be an in vivo target gene for NF-kappaB2/p100. [less ▲]

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See detailNF-kappa B: a new player in angiostatic therapy.
Tabruyn, Sébastien ULg; Griffioen, Arjan W

in Angiogenesis (2008), 11(1), 101-6

Angiogenesis is considered a promising target in the treatment of cancer. Most of the angiogenesis inhibitors in late-stage clinical testing or approved for the treatment of cancer act indirectly on ... [more ▼]

Angiogenesis is considered a promising target in the treatment of cancer. Most of the angiogenesis inhibitors in late-stage clinical testing or approved for the treatment of cancer act indirectly on endothelial cells. They either neutralize angiogenic growth factors from the circulation or block the signaling pathways activated by these growth factors. Another group of angiogenesis inhibitors are the direct angiostatic compounds. These agents have a direct effect on the endothelium, affecting cellular regulatory pathways, independently of the tumor cells. The reason that this category of agents is lagging behind regarding their translation to the clinic may be the lack of sufficient knowledge on the mechanism of action of these compounds. The transcription factor NF-kappaB has been recently connected with multiple aspects of angiogenesis. In addition, several recent studies report that angiogenesis inhibition is associated to NF-kappaB activation. This is of special interest since in tumor cells NF-kappaB activation has been associated to inhibition of apoptosis and currently novel treatment strategies are being developed based on inhibition of NF-kappaB. The paradigm that systemic NF-kappaB inhibition can serve as an anti-cancer strategy, therefore, might need to be re-evaluated. Based on recent data, it might be speculated that NF-kappaB activation, when performed specifically in endothelial cells, could be an efficient strategy for the treatment of cancer. [less ▲]

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See detailNF-kappaB activation by DNA damage
Habraken, Yvette ULg

Conference (2012, May 11)

L’importance de la kinase ATM pour l’activation du complexe IKK suite aux dommages à l’ADN a été démontrée par de nombreuses équipes. ATM est requis pour (i) la phosphorylation de NEMO, (ii) l’activation ... [more ▼]

L’importance de la kinase ATM pour l’activation du complexe IKK suite aux dommages à l’ADN a été démontrée par de nombreuses équipes. ATM est requis pour (i) la phosphorylation de NEMO, (ii) l’activation du complexe TAK1/Tab2 et (iii) l’induction de la poly-ubiquitination de TRAF6 ou RIP1 ou ELKS. Nos travaux ont permis la mise en évidence d’une quatrième fonction d’ATM en aval du complexe IKK. Après avoir montré qu’ATM phosphorylait de manière spécifique la sérine 547 de p65, nous avons observé que la mutation S547A n’affectait pas globalement le potentiel transactivateur du NF-kappaB mais réprimait de manière spécifique la transcription de certains gènes [CXCL1, CXCL2, CCL20, IL-8, TNF, Selectine E, V-CAM1, et, A20]. La transcription d’IκBα et de Cox2 n’est pas influencée par la mutation. L’étude du mécanisme moléculaire, au niveau du promoteur de l’IL8, a montré que la phosphorylation de S547 est responsable de l’interaction avec HDCA1 dont la présence au niveau du promoteur diminue l’acétylation de l’histone H3 et donc réduit la transcription. Ces résultats ont été obtenus en cellules HEK293 exprimant p65WT ou p65S547A exogène (porteur d’une mutation silencieuse les rendant résistants au siRNA utilisé pour éteindre le p65 endogène). [less ▲]

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See detailNF-kappaB activation in endothelial cells is critical for the activity of angiostatic agents.
Tabruyn, Sébastien ULg; Memet, Sylvie; Ave, Patrick et al

in Molecular Cancer Therapeutics (2009), 8(9), 2645-54

In tumor cells, the transcription factor NF-kappaB has been described to be antiapoptotic and proproliferative and involved in the production of angiogenic factors such as vascular endothelial growth ... [more ▼]

In tumor cells, the transcription factor NF-kappaB has been described to be antiapoptotic and proproliferative and involved in the production of angiogenic factors such as vascular endothelial growth factor. From these data, a protumorigenic role of NF-kappaB has emerged. Here, we examined in endothelial cells whether NF-kappaB signaling pathway is involved in mediating the angiostatic properties of angiogenesis inhibitors. The current report describes that biochemically unrelated agents with direct angiostatic effect induced NF-kappaB activation in endothelial cells. Our data showed that endostatin, anginex, angiostatin, and the 16-kDa N-terminal fragment of human prolactin induced NF-kappaB activation in endothelial cells in both cultured human endothelial cells and in vivo in a mouse tumor model. It was also found that NF-kappaB activity was required for the angiostatic activity, because inhibition of NF-kappaB in endothelial cells impaired the ability of angiostatic agents to block sprouting of endothelial cells and to overcome endothelial cell anergy. Therefore, activation of NF-kappaB in endothelial cells can result in an unexpected antitumor outcome. Based on these data, the current approach of systemic treatment with NF-kappaB inhibitors may therefore be revisited because NF-kappaB activation specifically targeted to endothelial cells might represent an efficient strategy for the treatment of cancer. [less ▲]

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See detailNf-Kappab Activation in Response to Toxical and Therapeutical Agents: Role in Inflammation and Cancer Treatment
Bours, Vincent ULg; Bonizzi, Giuseppina; Bentires-Alj, Mohamed et al

in Toxicology (2000), 153(1-3), 27-38

The NF-kappaB transcription factor is ubiquitously expressed and controls the expression of a large number of genes. Experimental data clearly indicate that NF-kappaB is a major regulator of the ... [more ▼]

The NF-kappaB transcription factor is ubiquitously expressed and controls the expression of a large number of genes. Experimental data clearly indicate that NF-kappaB is a major regulator of the inflammatory reaction by controlling the expression of pro-inflammatory molecules in response to cytokines, oxidative stress and infectious agents. We demonstrated that NF-kappaB activation by IL-1beta follows three distinct cell-specific pathways. Moreover, our studies indicated that in one model of inflammatory diseases, horse recurrent airway obstruction (RAO), the extent of NF-kappaB basal activity correlates with pulmonary dysfunction. Another role of NF-kappaB activity protects cancer cells against apoptosis and could participate in the resistance to cancer treatment. However, we did not observe any increased cytotoxicity after treatment with anticancer drugs or TNF-alpha of cells expressing a NF-kappaB inhibitor. Therefore, we can conclude that the inhibition of apoptosis by NF-kappaB is likely to be cell type and stimulus-dependent. Further studies are required to determine whether NF-kappaB could be a target for anticancer treatments. [less ▲]

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See detailNF-kappaB inducing kinase (NIK) inhibitors: identification of new scaffolds using virtual screening.
Mortier, Jeremie; Masereel, Bernard; Remouchamps, Caroline ULg et al

in Bioorganic & Medicinal Chemistry Letters (2010), 20(15), 4515-20

As a wide variety of pro-inflammatory cytokines are involved in the development of rheumatoid arthritis (RA), there is an urgent need for the discovery of novel therapeutic strategies. Among these, the ... [more ▼]

As a wide variety of pro-inflammatory cytokines are involved in the development of rheumatoid arthritis (RA), there is an urgent need for the discovery of novel therapeutic strategies. Among these, the inhibition of the NF-kappaB inducing kinase (NIK), a key enzyme of the NF-kappaB alternative pathway activation, represents a potential interesting approach. In fact, NIK is involved downstream of many tumor necrosis factor receptors (TNFR) like CD40, RANK or LTbetaR, implicated in the pathogenesis of RA. But, up to now, the number of reported putative NIK inhibitors is extremely limited. In this work, we report a virtual screening (VS) study combining various filters including high-throughput docking using a 3D-homology model and ranking by using different scoring functions. This work led to the identification of two molecular fragments, 4H-isoquinoline-1,3-dione (5) and 2,7-naphthydrine-1,3,6,8-tetrone (6) which inhibit NIK with an IC(50) value of 51 and 90 microM, respectively. This study opens new perspectives in the field of the NF-kappaB alternative pathway inhibition. [less ▲]

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See detailNF-kappaB inhibition improves the sensitivity of human glioblastoma cells to 5-aminolevulinic acid-based photodynamic therapy.
Coupienne, Isabelle ULg; Bontems, Sébastien ULg; Dewaele, M. et al

in Biochemical Pharmacology (2011)

Glioblastoma constitute the most frequent and deadliest brain tumors of astrocytic origin. They are very resistant to all current therapies and are associated with a huge rate of recurrence. In most cases ... [more ▼]

Glioblastoma constitute the most frequent and deadliest brain tumors of astrocytic origin. They are very resistant to all current therapies and are associated with a huge rate of recurrence. In most cases, this type of tumor is characterized by a constitutive activation of the nuclear factor-kappaB (NF-kappaB). This factor is known to be a key regulator of various physiological processes such as inflammation, immune response, cell growth or apoptosis. In the present study, we explored the role of NF-kappaB activation in the sensitivity of human glioblastoma cells to a treatment by 5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT). 5-ALA is a physiological compound widely used in PDT as well as in tumor photodetection (PDD). Our results show that inhibition of NF-kappaB improves glioblastoma cell death in response to 5-ALA-PDT. We then studied the molecular mechanisms underlying the cell death induced by PDT combined or not with NF-kappaB inhibition. We found that apoptosis was induced by PDT but in an incomplete manner and that, unexpectedly, NF-kappaB inhibition reduced its level. Oppositely PDT mainly induces necrosis in glioblastoma cells and NF-kappaB is found to have anti-necrotic functions in this context. The autophagic flux was also enhanced as a result of 5-ALA-PDT and we demonstrate that stimulation of autophagy acts as a pro-survival mechanism confering protection against PDT-mediated necrosis. These data point out that 5-ALA-PDT has an interesting potential as a mean to treat glioblastoma and that inhibition of NF-kappaB renders glioblastoma cells more sensitive to the treatment. [less ▲]

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See detailNF-kappaB transcription factor activation by hydrogen peroxide can be decreased by 2,3-dihydroxybenzoic acid and its ethylester derivative
Sappey, Christine; Boelaert, J. R.; Legrand-Poels, Sylvie ULg et al

in Archives of Biochemistry & Biophysics (1995)

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See detailNF-kappaB transcription factor and human immunodeficiency virus type 1 (HIV-1) are activated by methylene blue photosensitization
Piret, Bernard; Legrand-Poels, Sylvie ULg; Sappey, Christine et al

in European Journal of Biochemistry (1995)

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See detailNF-kappaB-induced KIAA1199 promotes survival through EGFR signalling.
Shostak, Kateryna ULg; Zhang, Xin; Hubert, Pascale ULg et al

in Nature communications (2014), 5

Constitutive activation of EGFR- and NF-kappaB-dependent pathways is a hallmark of cancer, yet signalling proteins that connect both oncogenic cascades are poorly characterized. Here we define KIAA1199 as ... [more ▼]

Constitutive activation of EGFR- and NF-kappaB-dependent pathways is a hallmark of cancer, yet signalling proteins that connect both oncogenic cascades are poorly characterized. Here we define KIAA1199 as a BCL-3- and p65-dependent gene in transformed keratinocytes. KIAA1199 expression is enhanced on human papillomavirus (HPV) infection and is aberrantly expressed in clinical cases of cervical (pre)neoplastic lesions. Mechanistically, KIAA1199 binds Plexin A2 and protects from Semaphorin 3A-mediated cell death by promoting EGFR stability and signalling. Moreover, KIAA1199 is an EGFR-binding protein and KIAA1199 deficiency impairs EGF-dependent Src, MEK1 and ERK1/2 phosphorylations. Therefore, EGFR stability and signalling to downstream kinases requires KIAA1199. As such, KIAA1199 promotes EGF-mediated epithelial-mesenchymal transition (EMT). Taken together, our data define KIAA1199 as an oncogenic protein induced by HPV infection and constitutive NF-kappaB activity that transmits pro-survival and invasive signals through EGFR signalling. [less ▲]

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See detailNF-kappaB: an important transcription factor in photobiology
Legrand-Poels, Sylvie ULg; Schoonbroodt, Sonia; Matroule, Jean-Yves et al

in Journal of Photochemistry and Photobiology B : Biology (1998)

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