Inhibition of nuclear factor kappa-B signaling reduces growth in XXXX in vivo.

@entity1 @entity9135 @entity1313 @entity5 @entity1749 @entity13373 @entity6108 @entity11 @entity8584 @entity3378 @entity2946
BACKGROUND: @entity2946 is a highly @entity1313 that requires surgery, whole brain and spine irradiation, and intense chemotherapy for treatment. A more sophisticated understanding of the pathophysiology of @entity2946 is needed to successfully reduce the intensity of treatment and improve outcomes. Nuclear factor kappa-B (NFkB) is a signaling pathway that controls transcriptional activation of genes important for tight regulation of many cellular processes and is aberrantly expressed in many types of @entity5 . METHODS: To test the importance of NFkB to @entity2946 cell growth, the effects of multiple drugs that inhibit NFkB, @entity13373 , @entity8584 , @entity3378 , @entity6108 and @entity1749 , were studied in @entity2946 cell lines compared to a @entity11 cell line and normal neurons. Expression of endogenous NFkB was investigated in cultured cells, xenograft @entity5 , and primary @entity1 @entity5 samples. A dominant negative construct for the endogenous inhibitor of NFkB, IkB, was prepared from @entity2946 cell lines and @entity5 were established to allow specific pathway inhibition. RESULTS: We report high constitutive activity of the canonical NFkB pathway, as seen by Western analysis of the NFkB subunit @entity9135 , in @entity5 compared to normal brain. The @entity9135 subunit of NFkB is extremely highly expressed in xenograft @entity5 from @entity1 @entity2946 cell lines; though, conversely, the same cells in culture have minimal expression without specific stimulation. We demonstrate that pharmacological inhibition of NFkB in cell lines halts proliferation and leads to apoptosis. We show by immunohistochemical stain that phosphorylated @entity9135 is found in the majority of @entity5 cells examined. Finally, expression of a dominant negative form of the endogenous inhibitor of NFkB, dnIkB, resulted in poor xenograft @entity5 growth, with average @entity5 volumes 40% smaller than controls. CONCLUSIONS: These data collectively demonstrate that NFkB signaling is important for @entity2946 @entity5 growth, and that inhibition can reduce @entity5 size and viability in vivo. We discuss the implications of NFkB signaling on the approach to managing @entity1 with @entity2946 in order to improve clinical outcomes.
