Activation of NF-KB Signaling by Inhibitor of NF-KB Kinase β Increases Aggressiveness of Ovarian Cancer

The NF-kappa B family of transcription factors has been implicated in the propagation of ovarian cancer, but the significance of constitutive NF-kappa B signaling in ovarian cancer is unknown. We hypothesized that constitutive NF-kappa B signaling defines a subset of ovarian cancer susceptible to therapeutic targeting of this pathway. We investigated the biological relevance of NF-kappa B in ovarian cancer using a small-molecule inhibitor of inhibitor of NF-kappa B kinase beta (IKK beta) and confirmed with RNA interference toward IKK beta. We developed a gene expression signature of IKK beta signaling in ovarian cancer using both pharmacologic and genetic manipulation of IKK beta. The expression of IKK beta protein itself and the nine-gene ovarian cancer-specific IKK beta signature were related to poor outcome in independently collected sets of primary ovarian cancers (P = 0.02). IKK beta signaling in ovarian cancer regulated the transcription of genes involved in a wide range of cellular effects known to increase the aggressive nature of the cells. We functionally validated the effect of IKK beta signaling on proliferation, invasion, and adhesion. Downregulating IKK beta activity, either by a small-molecule kinase inhibitor or by short hairpin RNA depletion of IKK beta, blocked all of these cellular functions, reflecting the negative regulation of the target genes identified. The diversity of functions controlled by IKK beta in ovarian cancer suggests that therapeutic blockade of this pathway could be efficacious if specific IKK beta inhibitor therapy is focused to patients whose tumors express a molecular profile suggestive of dependence on IKK beta activity. Cancer Res; 70(10); 4005-14. (C) 2010 AACR.