NF-κB Inducing Kinase, a Central Signaling Component of the Non-Canonical Pathway of NF-κB, Contributes to Ovarian Cancer Progression

Ovarian cancer is one of the leading causes of female death and the development of novel therapeutic approaches is urgently required. Nuclear factor-kappa B (NF-kappa B) is constitutively activated in several types of cancer including ovarian cancer and is known to support the survival of cancer cells. However, molecular mechanisms of persistent activation of NF-kappa B in ovarian cancer remain largely unknown. We report here that, in addition to the previously reported canonical activation, NF-kappa B is activated through the noncanonical pathway in ovarian cancer cells. RNA interference-mediated silencing of NF-kappa B inducing kinase (NIK), a central regulator of the noncanonical pathway, reduced the NF-kappa B2/p52 DNA binding activity and NF-kappa B-dependent reporter gene expression as well as NF-kappa B target gene expression. Notably, anchorage-dependent and independent cell growth was impaired in NIK-depleted cells. Depletion of NIK also suppressed tumor formation in the nude mouse xenograft assay. These results indicate that NIK plays a key role in constitutive NF-kB activation and the progression of ovarian cancer cells and suggest that NIK represents an attractive therapeutic target for ovarian cancer.