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

ABSTRACT: BACKGROUND: 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 (NF?B) 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. METHODS: To test the importance of NF?B to medulloblastoma cell growth, the effects of multiple drugs that inhibit NF?B, 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 NF?B was investigated in cultured cells, xenograft flank tumors, and primary human tumor samples. A dominant negative construct for the endogenous inhibitor of NF?B, I?B, was prepared from medulloblastoma cell lines and flank tumors were established to allow specific pathway inhibition. RESULTS: We report high constitutive activity of the canonical NF?B pathway, as seen by Western analysis of the NF?B subunit p65, in medulloblastoma tumors compared to normal brain. The p65 subunit of NF?B 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 NF?B 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 NF?B, dnI?B, resulted in poor xenograft tumor growth, with average tumor volumes 40% smaller than controls. CONCLUSIONS: These data collectively demonstrate that NF?B signaling is important for medulloblastoma tumor growth, and that inhibition can reduce tumor size and viability in vivo. We discuss the implications of NF?B signaling on the approach to managing patients with medulloblastoma in order to improve clinical outcomes.

SUBMITTER: Spiller SE 

PROVIDER: S-EPMC3094324 | biostudies-other | 2011

REPOSITORIES: biostudies-other