title: NIK controls classical and alternative NF-κB activation and is necessary for the survival of human T-cell lymphoma cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Lina
authors.initials: L
authors.lastname: Odqvist
authors.forename: Margarita
authors.initials: M
authors.lastname: Sánchez-Beato
authors.forename: Santiago
authors.initials: S
authors.lastname: Montes-Moreno
authors.forename: Esperanza
authors.initials: E
authors.lastname: Martín-Sánchez
authors.forename: Raquel
authors.initials: R
authors.lastname: Pajares
authors.forename: Lydia
authors.initials: L
authors.lastname: Sánchez-Verde
authors.forename: Pablo L
authors.initials: PL
authors.lastname: Ortiz-Romero
authors.forename: Jose
authors.initials: J
authors.lastname: Rodriguez
authors.forename: Socorro M
authors.initials: SM
authors.lastname: Rodríguez-Pinilla
authors.forename: Francisca
authors.initials: F
authors.lastname: Iniesta-Martínez
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Solera-Arroyo
authors.forename: Rafael
authors.initials: R
authors.lastname: Ramos-Asensio
authors.forename: Teresa
authors.initials: T
authors.lastname: Flores
authors.forename: Javier Menarguez
authors.initials: JM
authors.lastname: Palanca
authors.forename: Federico García
authors.initials: FG
authors.lastname: Bragado
authors.forename: Purificación Domínguez
authors.initials: PD
authors.lastname: Franjo
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D016399:Lymphoma, T-Cell / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000201:enzymology; D059467:Transcriptome; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D000097782:NF-kappaB-Inducing Kinase