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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 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 detailThe NF-kappaB transcription factor: structure, function and interaction with the oncoprotein Bcl-3.
Bours, Vincent ULg

Thèse d’agrégation de l’enseignement supérieur (1994)

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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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See detailNF-kB activity, and IL-8 and GM-CSF expression, in the milk of chorionic mastitis-affected cows
Boulanger, Delphine; Bureau, Fabrice ULg; Lekeux, Pierre ULg

in Pflügers Archiv : European Journal of Physiology (2002), 443

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See detailNF-kB activity, and IL-8 and GM-CSF expression, in the milk of chorionic mastitis-affected cows
Boulanger, Delphine; Bureau, Fabrice ULg; Lekeux, Pierre ULg

in National Mastitis Council Proceedings (2002)

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See detailNF-kB activity, and IL-8 and GM-CSF expression, in the milk of chronic mastitis-affected cows
Boulanger, D.; Bureau, Fabrice ULg; Lekeux, Pierre ULg

in Proceedings : National Mastitis Council, 41st Annual Meeting (2002)

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See detailNF-kB, stem cells and breast cancer: the links get stronger
Shostak, Kateryna ULg; Chariot, Alain ULg

in Breast Cancer Research [=BCR] (2011), 13(4), 214

Self-renewing breast cancer stem cells are key actors in perpetuating tumour existence and in treatment resistance and relapse. The molecular pathways required for their maintenance are starting to be ... [more ▼]

Self-renewing breast cancer stem cells are key actors in perpetuating tumour existence and in treatment resistance and relapse. The molecular pathways required for their maintenance are starting to be elucidated. Among them is the transcription factor NF-κB, which is known to play critical roles in cell survival, inflammation and immunity. Recent studies indicate that mammary epithelial NF-κB regulates the self-renewal of breast cancer stem cells in a model of Her2-dependent tumourigenesis. We will describe here the NF-κB-activating pathways that are involved in this process and in which progenitor cells this transcription factor is actually activated. [less ▲]

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See detailNF-kB-dependent cytokine production is abolished by cyclopentenone prostaglandins in lung epithelial cells
Bureau, Fabrice ULg

in Proceedings: Annual Congress of the European Respiratory Society (2001)

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See detailThe NF-κ B-independent functions of IKK subunits in immunity and cancer
Chariot, Alain ULg

in Trends in Cell Biology (2009), 19

The IKK complex is involved in transcriptional activation by phosphorylating the inhibitory molecule IkBa, a modification that triggers its subsequent degradation, allowing activation of NF-kB ... [more ▼]

The IKK complex is involved in transcriptional activation by phosphorylating the inhibitory molecule IkBa, a modification that triggers its subsequent degradation, allowing activation of NF-kB. Importantly, recent reports indicate that multiple cytoplasmic and nuclear proteins distinct from the NF-kB/IkB proteins are phosphorylated by the catalytic subunits of the IKK complex, IKKa or IKKb. Here we describe how the IKK subunits can play crucial roles in allergy, inflammation, immunity by targeting proteins such as SNAP23 and IRF7 but also in cancer by phosphorylating key molecules such as p53, TSC1 and FOXO3a through NF-kB-independent pathways. Thus, these recent findings considerably widen the biological roles played by these kinases and suggest that a full understanding of the biological roles played by IKKa and IKKb requires an exhaustive characterization of their substrates. [less ▲]

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See detailNF-κB transcription factor induces drug resistance through MDR1 expression in cancer cells
Bentires-Alj, Mohamed; Barbu, Véronique; Fillet, Marianne ULg et al

in Oncogene (2003), 22

The ubiquitous NF-kappaB transcription factor has been reported to inhibit apoptosis and to induce drug resistance in cancer cells. Drug resistance is the major reason for cancer therapy failure and ... [more ▼]

The ubiquitous NF-kappaB transcription factor has been reported to inhibit apoptosis and to induce drug resistance in cancer cells. Drug resistance is the major reason for cancer therapy failure and neoplastic cells often develop multiple mechanisms of drug resistance during tumor progression. We observed that NF-kappaB or P-glycoprotein inhibition in the HCT15 colon cancer cells led to increased apoptotic cell death in response to daunomycin treatment. Interestingly, NF-kappaB inhibition through transfection of a plasmid coding for a mutated IkappaB-alpha inhibitor increased daunomycin cell uptake. Indeed, the inhibition of NF-kappaB reduced mdr1 mRNA and P-glycoprotein expression in HCT15 cells. We identified a consensus NF-kappaB binding site in the first intron of the human mdr1 gene and demonstrated that NF-kappaB complexes could bind with this intronic site. Moreover, NF-kappaB transactivates an mdr1 promoter luciferase construct. Our data thus demonstrate a role for NF-kappaB in the regulation of the mdr1 gene expression in cancer cells and in drug resistance. [less ▲]

Detailed reference viewed: 84 (9 ULg)