The lymphotoxin-β receptor is an upstream activator of NF-κB-mediated transcription in melanoma cells

The pleiotropic transcription factor nuclear factor-kappa B (NF-kappa B (p50/p65)) regulates the transcription of genes involved in the modulation of cell proliferation, apoptosis, and oncogenesis. Furthermore, a host of solid and hematopoietic tumor types exhibit constitutive activation of NF-kappa B (Basseres, D. S., and Baldwin, A. S. (2006) 25,6817-6830). However, the mechanism for this constitutive activation of NF-kappa B has not been elucidated in the tumors. We have previously shown that NF-kappa B-inducing kinase (NIK) protein and its association with Inhibitor of kappa B kinase alpha beta are elevated in melanoma cells compared with their normal counterpart, leading to constitutive activation of NF-kappa B. Moreover, expression of dominant negative NIK blocked this base-line NF-kappa B activity in melanoma cells. Of the three receptors that require NIK for activation of NF-kappa B only the lymphotoxin-beta receptor (LT beta-R) is expressed in melanoma. We show in this manuscript that for melanoma there is a strong relationship between expression of the LT beta-R and constitutive NF-kappa B transcriptional activity. Moreover, we show that activation of the LT beta-R can drive NF-kappa B. activity to regulate gene expression that leads to enhanced cell growth. The inhibition by LT beta-R shRNA resulted in decreased NF-kappa B promoter activity, decreased growth, and decreased invasiveness as compared with control. These results indicate that the LT beta-R constitutively induces NF-kappa B activation, and this event maybe associated with autonomous growth of melanoma cells.