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

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 tre...

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Autores principales: Spiller, Susan E, Logsdon, Naomi J, Deckard, Lindsey A, Sontheimer, Harald
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094324/
https://www.ncbi.nlm.nih.gov/pubmed/21492457
http://dx.doi.org/10.1186/1471-2407-11-136
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author Spiller, Susan E
Logsdon, Naomi J
Deckard, Lindsey A
Sontheimer, Harald
author_facet Spiller, Susan E
Logsdon, Naomi J
Deckard, Lindsey A
Sontheimer, Harald
author_sort Spiller, Susan E
collection PubMed
description 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 (NFκB) 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 NFκB to medulloblastoma cell growth, the effects of multiple drugs that inhibit NFκB, 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 NFκB was investigated in cultured cells, xenograft flank tumors, and primary human tumor samples. A dominant negative construct for the endogenous inhibitor of NFκB, IκB, 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 NFκB pathway, as seen by Western analysis of the NFκB subunit p65, in medulloblastoma tumors compared to normal brain. The p65 subunit of NFκB 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 NFκB 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 NFκB, dnIκB, resulted in poor xenograft tumor growth, with average tumor volumes 40% smaller than controls. CONCLUSIONS: These data collectively demonstrate that NFκB signaling is important for medulloblastoma tumor growth, and that inhibition can reduce tumor size and viability in vivo. We discuss the implications of NFκB signaling on the approach to managing patients with medulloblastoma in order to improve clinical outcomes.
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spelling pubmed-30943242011-05-14 Inhibition of nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo Spiller, Susan E Logsdon, Naomi J Deckard, Lindsey A Sontheimer, Harald BMC Cancer Research Article 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 (NFκB) 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 NFκB to medulloblastoma cell growth, the effects of multiple drugs that inhibit NFκB, 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 NFκB was investigated in cultured cells, xenograft flank tumors, and primary human tumor samples. A dominant negative construct for the endogenous inhibitor of NFκB, IκB, 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 NFκB pathway, as seen by Western analysis of the NFκB subunit p65, in medulloblastoma tumors compared to normal brain. The p65 subunit of NFκB 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 NFκB 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 NFκB, dnIκB, resulted in poor xenograft tumor growth, with average tumor volumes 40% smaller than controls. CONCLUSIONS: These data collectively demonstrate that NFκB signaling is important for medulloblastoma tumor growth, and that inhibition can reduce tumor size and viability in vivo. We discuss the implications of NFκB signaling on the approach to managing patients with medulloblastoma in order to improve clinical outcomes. BioMed Central 2011-04-14 /pmc/articles/PMC3094324/ /pubmed/21492457 http://dx.doi.org/10.1186/1471-2407-11-136 Text en Copyright ©2011 Spiller et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Spiller, Susan E
Logsdon, Naomi J
Deckard, Lindsey A
Sontheimer, Harald
Inhibition of nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo
title Inhibition of nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo
title_full Inhibition of nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo
title_fullStr Inhibition of nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo
title_full_unstemmed Inhibition of nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo
title_short Inhibition of nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo
title_sort inhibition of nuclear factor kappa-b signaling reduces growth in medulloblastoma in vivo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094324/
https://www.ncbi.nlm.nih.gov/pubmed/21492457
http://dx.doi.org/10.1186/1471-2407-11-136
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