The NF-κB-Inducing Kinase (NIK) Is Involved in Both Classical and Alternative NF-κB Activation and Is Necessary for the Survival of T Cell Lymphoma Cells,

Abstract 3665

Nuclear factor κB (NF-κB) signaling has a critical role in the development and progression of several types of cancers. T cell lymphomas have been associated with NF-κB activity and its inhibition has been suggested as a possible therapeutic strategy to be further evaluated. However, the causes of NF-κB activation and the importance of this signaling pathway in T cell lymphomagenesis are still poorly understood. The NF-κB-inducing kinase, NIK, is a serine/threonine kinase that is crucial for the activation of the alternative NF-κB pathway but can also be involved in classical pathway activation. We evaluated the expression of nuclear p50 (classical NF-κB activation) and p52 (alternative NF-κB activation) in 30 primary T cell lymphoma samples and observed that 80.0% and 80.6% of cases showed nuclear staining of p50 and p52, respectively. Subsequently, using T-cell lymphoma cell lines, we investigated whether this classical and alternative NF-κB activation could be dependent on NIK expression. A strong overexpression of NIK mRNA in T cell lymphoma cell lines, compared to purified healthy donor T cells, was observed. This overexpression was associated with both classical (nuclear p50 and p65) and alternative (nuclear p52 and RelB) NF-κB activation. Knockdown of NIK in T cell lymphoma cells resulted in decreased processing of both p100 and p105, as well as a decrease in DNA binding activity of both classical and alternative NF-κB members. Furthermore, NIK knockdown lead to a dramatic increase in cell death in NIK overexpressing T cell lymphoma cell lines. These results suggest that NIK is involved in both classical and alternative NF-κB activation and is a putative therapeutic target in T cell lymphomas.