IKK-i/IKKε controls constitutive, cancer cell-associated NF-κB activity via regulation of Ser-536 p65/RelA phosphorylation

Nuclear factor kappa B(NF-kappa B) has been studied extensively as an inducible transcriptional regulator of the immune and inflammatory response. NF-kappa B activation downstream of lipopolysaccharide or cytokine stimulation is controlled by the I kappa B kinase complex, which contains IKK alpha and IKK beta. Significantly, the constitutive activity of NF-kappa B has been implicated as an important aspect of many cancer cells, but mechanisms associated with this activity are poorly understood. An inducible kinase, IKK-i/IKK epsilon, related to the catalytic forms of the I kappa B kinase, has been studied as an anti-viral, innate immune regulator through its ability to control the activity of the transcription factors IRF-3 and IRF-7. Here, we demonstrate that IKK-i/IKK epsilon is expressed in a number of cancer cells and is involved in regulating NF-kappa B activity through its ability to control basal/constitutive, but not cytokine-induced, p65/RelA phosphorylation at Ser-536, a modification proposed to contribute to the transactivation function of NF-kappa B. Knockdown of IKK-i/IKK epsilon or expression of a S536A mutant form of p65 suppresses HeLa cell proliferation. The data indicate a role for IKK-i/IKK epsilon in controlling proliferation of certain cancer cells through regulation of constitutive NF-kappa B activity.