Overexpressed NF-κB-inducing kinase contributes to the tumorigenesis of adult T-cell leukemia and Hodgkin Reed-Sternberg cells

The nuclear factor-kappa B (NF-kappa B) transcription factors play important roles in cancer development by preventing apoptosis and facilitating the tumor cell growth. However, the precise mechanisms by which NF-kappa B is constitutively activated in specific cancer cells remain largely unknown. In our current study, we now report that NF-kappa B-inducing kinase (NIK) is overexpressed at the pretranslational level in adult T-cell leukemia (ATL) and Hodgkin Reed-Sternberg cells (H-RS) that do not express viral regulatory proteins. The overexpression of NIK causes cell transformation in rat fibroblasts, which is abolished by a super-repressor form of I kappa B alpha.. Notably, depletion of NIK in ATL cells by RNA interference reduces the DNA-binding activity of NF-kappa B and NF-kappa B-dependent transcriptional activity, and efficiently suppresses tumor growth in NOD/SCID/gamma c(null) mice. These results indicate that the deregulated expression of NIK plays a critical role in constitutive NF-kappa B activation in ATL and H-RS cells, and suggest also that NIK is an attractive molecular target for cancer therapy.