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

Abstract

Ovarian cancer is one of the leading causes of female death and the development of novel therapeutic approaches is urgently required. Nuclear factor-κB (NF-κB) 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-κB in ovarian cancer remain largely unknown. We report here that, in addition to the previously reported canonical activation, NF-κB is activated through the noncanonical pathway in ovarian cancer cells. RNA interference-mediated silencing of NF-κB inducing kinase (NIK), a central regulator of the noncanonical pathway, reduced the NF-κB2/p52 DNA binding activity and NF-κB-dependent reporter gene expression as well as NF-κB 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-κB activation and the progression of ovarian cancer cells and suggest that NIK represents an attractive therapeutic target for ovarian cancer.

Lymphotoxin‐β receptor‐NIK signaling induces alternative RELB/NF‐κB2 activation to promote metastatic gene expression and cell migration in head and neck cancer

“…NIK has been reported to be the downstream kinase of LTβR in the alternative NF‐κB pathway, and LTβ/LTβR binding enhances NIK stability . We demonstrated here that targeting of NIK either by siRNA or small molecule inhibitor 1, 3[2H, 4H]‐Isoquinolinedione attenuates protein expression of NIK, p‐IKKα, NF‐κB2(p100/p52), and RELB as well as nuclear translocation of NF‐κB2 and RELB (Figures C, D, and A, B).…”

Dendritic cells require NIK for CD40-dependent cross-priming of CD8 + T cells

“…NIK has been considered clinically as a potential oncology target, because some cancers appear to depend on constitutive NIK activation for survival and growth (31,32). Our findings raise the possibility that targeting NIK in an oncology setting also might alter the induction or maintenance of cell-mediated immunity, conceivably with negative or positive consequences on disease course, depending on how this alteration affects the balance of cancer immunity to tolerance.…”

TNF-α-Induced cPLA2 Expression via NADPH Oxidase/Reactive Oxygen Species-Dependent NF-κB Cascade on Human Pulmonary Alveolar Epithelial Cells

“…The signaling mechanisms mediated activation of NF-κB includes canonical and non-canonical pathways (Tak and Firestein, 2001). The canonical pathway has been well documented to regulate the pathophysiological functions; however, the non-canonical NF-κB-inducing kinase (NIK) pathway is not well understood in the expression of inflammatory genes (Uno et al, 2014). NIK plays central roles in the activation of non-canonical NF-κB pathway (Tak and Firestein, 2001; Uno et al, 2014).…”