title: The biological and clinical impact of inhibition of NF-κB-initiated apoptosis in diffuse large B cell lymphoma (DLBCL).
abstract: NF-κB is frequently over-expressed in a variety of non-Hodgkin's lymphomas (NHLs) and has been implicated in lymphomagenesis; however, its role in diffuse large B cell lymphoma (DLBCL) as a prognostic biomarker has not been fully elucidated. Therefore, we investigated the role of NF-κB and its association with clinicopathological features in a tissue microarray cohort of 230 DLBCL patient samples. We then elucidated the role of NF-κB inhibition on cell viability and apoptosis in vitro, using DLBCL cell lines. Using immunohistochemistry, NF-κB was detected in 25.6% (52/203) DLBCL tumours, was associated with activated B cell (ABC) phenotype (p = 0.0054), Epstein-Barr virus (EBV; p = 0.0080) and over-expression of the anti-apoptotic marker XIAP (p = 0.0013). DLBCL cases with nuclear expression of NF-κB showed a significantly poorer overall survival as compared to those without NF-κB expression (p = 0.0236). In a multivariate analysis using a Cox proportional hazard model for IPI and NF-κB expression, the relative risk was 2.97 for high NF-κB expression (95% CI 1.27-6.94; p = 0.0113) and 7.55 for the high-IPI group (95% CI 3.34-18.35; p < 0.0001). In vitro, Bay 11-7085 inhibited constitutively active NF-κB expression in a dose-dependent manner and inhibition of NF-κB also down-regulated expression of the downstream target gene products Bcl-2, Bcl-XL (BCL2L1), XIAP and Survivin, leading to apoptosis via activation of the mitochondrial apoptotic pathway. NF-κB over-expression was found to be an independent prognostic marker for poor survival in DLBCL. Altogether, these results suggest that NF-κB may be a useful prognostic biomarker and a potential target for therapeutic intervention in DLBCL.
authors.affiliation: Human Cancer Genomic Research, Research Center, King Fahad National Center for Children's Cancer, Riyadh, Saudi Arabia.
authors.forename: Prashant
authors.initials: P
authors.lastname: Bavi
authors.forename: Shahab
authors.initials: S
authors.lastname: Uddin
authors.forename: Rong
authors.initials: R
authors.lastname: Bu
authors.forename: Maqbool
authors.initials: M
authors.lastname: Ahmed
authors.forename: Jehad
authors.initials: J
authors.lastname: Abubaker
authors.forename: Valorie
authors.initials: V
authors.lastname: Balde
authors.forename: Zeeshan
authors.initials: Z
authors.lastname: Qadri
authors.forename: Dahish
authors.initials: D
authors.lastname: Ajarim
authors.forename: Fouad
authors.initials: F
authors.lastname: Al-Dayel
authors.forename: Azhar R
authors.initials: AR
authors.lastname: Hussain
authors.forename: Khawla S
authors.initials: KS
authors.lastname: Al-Kuraya
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D011379:Prognosis; D013450:Sulfones / Q000494:pharmacology; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; D020169:Caspases