IKK-ε Coordinates Invasion and Metastasis of Ovarian Cancer

Inhibitor of I kappa B kinases (IKK) are key regulators of NF-kappa B signaling. Three IKK isoforms-alpha, beta, and epsilon-have been linked to oncogenesis, yet the precise components of NF-kappa B signaling in ovarian cancer have not yet been dissected. We surveyed 120 ovarian cancer specimens for IKK-epsilon expression. Notably, cytoplasmic expression was elevated in metastatic lesions relative to primary tumors (P=0.03). Therefore, we hypothesized that IKK-epsilon drives ovarian cancer metastasis. IKK-epsilon was identified previously as a breast cancer oncogene and was associated with poor clinical outcome in ovarian cancer. We now define an ovarian cancer-specific IKK-epsilon-regulated gene expression signature using stably expressed short hairpin RNA targeting IKK-epsilon. Pathway analysis of the signature indicated that IKK-epsilon regulates expression of genes involved in cell motility and inflammation. We further showed that IKK-epsilon depletion in metastatic ovarian cancer cell lines decreased growth, adhesion, and invasion. Consistently, human xenografts depleted of IKK-epsilon in mice showed decreased aggressiveness, whereas overexpression of IKK-epsilon in a less invasive ovarian cancer cell line increased metastasis in vivo. Taken together, these data provide evidence that IKK-epsilon is a key coordinator of invasion and metastasis programs in ovarian cancer. Inhibition of IKK-epsilon signaling thus emerges as a viable therapeutic strategy in women whose ovarian cancer shows aberrant activation of this pathway. Cancer Res; 72(21); 5494-504. (C)2012 AACR.