Abstract C158: IKKβ inhibition modulates NF-κB signaling and decreases aggressiveness of ovarian cancer

Abstract

Abstract The NF-κB family of transcription factors has been implicated in the propagation of ovarian cancer, but the significance of constitutive NF-κB signaling in ovarian cancer is unknown. We hypothesized that constitutive NF-κB signaling defines a subset of ovarian cancer susceptible to therapeutic targeting of this pathway. To this end, we investigated the biological relevance of NF-κB in ovarian cancer cell lines using a small molecule inhibitor of IKKβ, and confirmed with RNA interference using stably expressed short hairpin RNA molecules towards IKKβ. We demonstrate here that the expression of IKKβ protein itself and the ovarian cancer-specific signature of IKKβ-regulated genes are related to poor outcome in independently collected sets of primary ovarian cancers. IKKβ signaling in ovarian cancer regulates 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 IKKβ signaling on proliferation, invasion and adhesion in ovarian cancer cell lines. IKKβ was involved in all of these cellular functions, reflecting its modulation of the target genes identified. The diversity of functions controlled by IKKβ in ovarian cancer suggest that therapy targeted to this pathway could be efficacious if specific IKKβ inhibitor therapy is focused to patients whose tumors express a molecular profile suggestive of dependence on IKKβ activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C158.