Background: Drug resistance is a major problem in ovarian cancer. Triggering apoptosis using death ligands such as tumour necrosis factor-related apoptosis inducing ligand (TRAIL) might overcome chemoresistance. Methods: We investigated whether acquired cisplatin resistance affects sensitivity to recombinant human (rh) TRAIL alone or in combination with cisplatin in an ovarian cancer cell line model consisting of A2780 and its cisplatin-resistant subline CP70. Results: Combining cisplatin and rhTRAIL strongly enhanced apoptosis in both cell lines. CP70 expressed less caspase 8 protein, whereas mRNA levels were similar compared with A2780. Pre-exposure of particularly CP70 to cisplatin resulted in strongly elevated caspase 8 protein and mRNA levels. Caspase 8 mRNA turnover and protein stability in the presence or absence of cisplatin did not differ between both cell lines. Cisplatin-induced caspase 8 protein levels were essential for the rhTRAIL-sensitising effect as demonstrated using caspase 8 small-interfering RNA (siRNA) and caspase-8 overexpressing constructs. Cellular FLICE-inhibitory protein (c-FLIP) and p53 siRNA experiments showed that neither an altered caspase 8/c-FLIP ratio nor a p53-dependent increase in DR5 membrane expression following cisplatin were involved in rhTRAIL sensitisation. Conclusion: Cisplatin enhances rhTRAIL-induced apoptosis in cisplatin-resistant ovarian cancer cells, and induction of caspase 8 protein expression is the key factor of rhTRAIL sensitisation. © 2011 Cancer Research UK All rights reserved.
DOCUMENT
BACKGROUND: Glucocorticoids (GCs) control expression of a large number of genes via binding to the GC receptor (GR). Transcription may be regulated either by binding of the GR dimer to DNA regulatory elements or by protein-protein interactions of GR monomers with other transcription factors. Although the type of regulation for a number of individual target genes is known, the relative contribution of both mechanisms to the regulation of the entire transcriptional program remains elusive. To study the importance of GR dimerization in the regulation of gene expression, we performed gene expression profiling of livers of prednisolone-treated wild type (WT) and mice that have lost the ability to form GR dimers (GRdim).RESULTS: The GR target genes identified in WT mice were predominantly related to glucose metabolism, the cell cycle, apoptosis and inflammation. In GRdim mice, the level of prednisolone-induced gene expression was significantly reduced compared to WT, but not completely absent. Interestingly, for a set of genes, involved in cell cycle and apoptosis processes and strongly related to Foxo3a and p53, induction by prednisolone was completely abolished in GRdim mice. In contrast, glucose metabolism-related genes were still modestly upregulated in GRdim mice upon prednisolone treatment. Finally, we identified several novel GC-inducible genes from which Fam107a, a putative histone acetyltransferase complex interacting protein, was most strongly dependent on GR dimerization.CONCLUSIONS: This study on prednisolone-induced effects in livers of WT and GRdim mice identified a number of interesting candidate genes and pathways regulated by GR dimers and sheds new light onto the complex transcriptional regulation of liver function by GCs.
DOCUMENT
In this paper we position sustainable tourism of the Wadden. The aim is to clarify the complex issues at stake and therewith provide a framework for future actions and policies.
DOCUMENT
Het project “Sporttoerisme - Sportas Amsterdam” draait om de vraag: welke kansen biedt sporttoerisme voor Sportas? De aanleiding voor het project is het bredere programma rond het gebiedsconcept Sportas Amsterdam. Dit programma behelst de ambitie van de gemeente Amsterdam, gemeente Amstelveen en partners om één ruimtelijk geheel te maken van het gebied en de sportfaciliteiten die in zuidwest Amsterdam zijn gelegen, grofweg van het Olympische Stadion tot en met de sportfaciliteiten in het Amsterdamse Bos. Het programma draagt bij aan city branding (regio Amsterdam), lokale bedrijfsontwikkeling (o.a. horeca, retail, dienstverlening), ondersteunen lokaal verenigingsleven en sportfaciliteiten (vitaliteit kantines en accommodatie), veiligheid (ruimtelijke eenheid, levendig) en leefbaarheid (toegankelijke en aantrekkelijke openbare ruimte). Bovenal kan de Sportas bijdragen aan het aantrekken en binden van de relatief hoogopgeleide en weinig plaatsgebonden leeftijdsgroep van 18-35 jaar. Dit sluit aan bij de ideeën van auteurs als Richard Florida (“The rise of the creative class”) en Charles Landry (“The art of city making”) over het aantrekken en vasthouden van de creatieve klasse en de kenniswerker. Het idee van de Sportas veronderstelt een transitie, van een versnipperd sportgebied naar geïntegreerd vrijetijdslandschap. Het gebied is momenteel al interessant voor sporttoerisme (topsport, breedtesport) en kan door deze transitie een impuls krijgen. Tegelijkertijd is de ontwikkeling van sporttoerisme een schakel in deze transitie. Er is echter nog te weinig bekend over de omvang van sporttoerisme en de potenties van de Sportas op dit vlak.
DOCUMENT
