NIK controls classical and alternative NF-κB activation and is necessary for the survival of human T-cell lymphoma cells.
| Autor: | Odqvist L; Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Sánchez-Beato M, Montes-Moreno S, Martín-Sánchez E, Pajares R, Sánchez-Verde L, Ortiz-Romero PL, Rodriguez J, Rodríguez-Pinilla SM, Iniesta-Martínez F, Solera-Arroyo JC, Ramos-Asensio R, Flores T, Palanca JM, Bragado FG, Franjo PD, Piris MA |
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| Jazyk: | angličtina |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2013 May 01; Vol. 19 (9), pp. 2319-30. Date of Electronic Publication: 2013 Mar 27. |
| DOI: | 10.1158/1078-0432.CCR-12-3151 |
| Abstrakt: | Purpose: Peripheral T-cell lymphomas (PTCL) are a heterogeneous entity of neoplasms with poor prognosis, a lack of effective therapies, and a largely unknown molecular pathology. Deregulated NF-κB activity has been associated with several lymphoproliferative diseases, but its importance in T-cell lymphomagenesis is poorly understood. We investigated the function of the NF-κB-inducing kinase (NIK), in this pathway and its role as a potential molecular target in T-cell lymphomas. Experimental Design: We used immunohistochemistry to analyze the expression of different NF-κB members in primary human PTCL samples and to study its clinical impact. With the aim of inhibiting the pathway, we used genetic silencing of NIK in several T-cell lymphoma cell lines and observed its effect on downstream targets and cell viability. Results: We showed that the NF-κB pathway was activated in a subset of PTCLs associated with poor overall survival. NIK was overexpressed in a number of PTCL cell lines and primary samples, and a pivotal role for NIK in the survival of these tumor cells was unveiled. NIK depletion led to a dramatic induction of apoptosis in NIK-overexpressing cell lines and also showed a more pronounced effect on cell survival than inhibitor of kappa B kinase (IKK) knockdown. NIK silencing induced a blockage of both classical and alternative NF-κB activation and reduced expression of several prosurvival and antiapoptotic factors. Conclusions: The results of the present study indicate that NIK could be a promising therapeutic target in these aggressive malignancies. (©2013 AACR.) |
| Databáze: | MEDLINE |
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