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Blockade of the NFκB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo

Oncogene volume 30, pages 3537–3548 (2011)Cite this article

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Abstract

Glioblastoma multiforme is one of the most devastating cancers and presents unique challenges to therapy because of its aggressive behavior. Cancer-initiating or progenitor cells have been described to be the only cell population with tumorigenic capacity in glioblastoma. Therefore, effective therapeutic strategies targeting these cells or the early precursors may be beneficial. We have established different cultures of glioblastoma-initiating cells (GICs) derived from surgical specimens and found that, after induction of differentiation, the NFκB transcriptional pathway was activated, as determined by analyzing key proteins such as p65 and IκB and the upregulation of a number of target genes. We also showed that blockade of nuclear factor (NF)κB signaling in differentiating GICs by different genetic strategies or treatment with small-molecule inhibitors, promoted replication arrest and senescence. This effect was partly mediated by reduced levels of the NFκB target gene cyclin D1, because its downregulation by RNA interference reproduced a similar phenotype. Furthermore, these results were confirmed in a xenograft model. Intravenous treatment of immunodeficient mice bearing human GIC-derived tumors with a novel small-molecule inhibitor of the NFκB pathway induced senescence of tumor cells but no ultrastructural alterations of the brain parenchyma were detected. These findings reveal that activation of NFκB may keep differentiating GICs from acquiring a mature postmitotic phenotype, thus allowing cell proliferation, and support the rationale for therapeutic strategies aimed to promote premature senescence of differentiating GICs by blocking key factors within the NFκB pathway.

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Acknowledgements

This work was supported by Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation) grants RD06/0020/0074 (JLF-L) and RD06/0020/0088 (JAM-C) (Red Temática de Investigación Cooperativa en Cáncer), PI070196, PI081878, and Accion Transversal del Cancer 2008, and grant API08/01 from Fundacion Marques de Valdecilla (JLF-L). We thank Francisco Moris (EntreChem, Spain) for providing the NFκB inhibitor 70124, and Ainara Sagardoy, Silvia Mora, Maria Collantes and Ivan Peñuelas (University of Navarra, Spain) for support with intracraneal injections and microPET studies.

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Authors and Affiliations

  1. Molecular Genetics Unit, Hospital Valdecilla, and Instituto de Formacion e Investigacion Marques de Valdecilla (IFIMAV), Av Cardenal Herrera Oria s/n, Santander, Spain

    L Nogueira, P Ruiz-Ontañon, L Grande & J L Fernandez-Luna

  2. Service of Neurosurgery, Hospital Valdecilla, Av Valdecilla s/n, Santander, Spain

    A Vazquez-Barquero & D Suarez

  3. Department of Anatomy and Cell Biology, and Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas, University of Cantabria-IFIMAV, Santander, Spain

    M Lafarga, M T Berciano & I Casafont

  4. Division of Oncology,Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    B Aldaz, E F Robles & J A Martinez-Climent

  5. Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    V Segura

  6. PharmaMar, Madrid, Spain

    L F Garcia

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  1. L Nogueira
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Correspondence to J L Fernandez-Luna.

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Nogueira, L., Ruiz-Ontañon, P., Vazquez-Barquero, A. et al. Blockade of the NFκB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo. Oncogene 30, 3537–3548 (2011). https://doi.org/10.1038/onc.2011.74

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