Inhibition of nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo
| Autor: | Harald Sontheimer, Naomi J. Logsdon, Lindsey A. Deckard, Susan E Spiller |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Pathology Pyrrolidines Bortezomib chemistry.chemical_compound Mice 0302 clinical medicine Pyrrolidine dithiocarbamate Transgenes 0303 health sciences NF-kappa B lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Primary tumor Boronic Acids 3. Good health Tumor Burden Oncology 030220 oncology & carcinogenesis Pyrazines I-kappa B Proteins Stem cell Signal transduction Ditiocarb Research Article Signal Transduction medicine.medical_specialty Curcumin Mice Nude Cell Growth Processes lcsh:RC254-282 03 medical and health sciences Thiocarbamates Cell Line Tumor Genetics medicine Animals Humans Cerebellar Neoplasms 030304 developmental biology Medulloblastoma Cell growth business.industry medicine.disease NFKB1 Xenograft Model Antitumor Assays Mice Inbred C57BL Sulfasalazine chemistry Cell culture Cancer research business |
| Zdroj: | BMC Cancer BMC Cancer, Vol 11, Iss 1, p 136 (2011) |
| ISSN: | 1471-2407 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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