Medulloblastoma is a highly malignant pediatric brain tumor that requires surgery, whole brain and spine irradiation, and intense chemotherapy for treatment. A more sophisticated understanding of the pathophysiology of medulloblastoma 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 cancer.

To test the importance of NFkB to medulloblastoma cell growth, the effects of multiple drugs that inhibit NFkappaB, pyrrolidine dithiocarbamate, diethyldithiocarbamate, sulfasalazine, curcumin and bortezomib, were studied in medulloblastoma cell lines compared to a malignant glioma cell line and normal neurons. Expression of endogenous NFkappaB was investigated in cultured cells, xenograft flank tumors, and primary human tumor samples. A dominant negative construct for the endogenous inhibitor of NFkB, IkB, was prepared from medulloblastoma cell lines and flank tumors were established to allow specific pathway inhibition.

We report high constitutive activity of the canonical NFkB pathway, as seen by Western analysis of the NFkB subunit p65, in medulloblastoma tumors compared to normal brain. The p65 subunit of NFkB is extremely highly expressed in xenograft tumors from human medulloblastoma 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 p65 is found in the majority of primary tumor cells examined. Finally, expression of a dominant negative form of the endogenous inhibitor of NFkB, dnIkB resulted in poor xenograft tumor growth, with average tumor volumes 40% smaller than controls.

These data collectively demonstrate that NFkB signaling is important for medulloblastoma tumor growth, and that inhibition can reduce tumor size and viability in vivo. We discuss the implications of NFkB signaling on the approach to managing patients with medulloblastoma in order to improve clinical outcomes.

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