Sustained Ikk Beta Phosphorylation And Nf-Kappa B Activation By Superoxide-Induced Peroxynitrite-Mediated Nitrotyrosine Modification Of B56 Gamma 3 And Pp2a Inactivation

Apart from its physiological role in inflammation and immunity, the nuclear factor-kappa B (NF-kappa B) protein complex has been implicated in tumorigenesis and its progression. Here, we provide evidence that a pro-oxidant milieu is an upstream effector of oncogenic NF-kappa B signaling. Through pharmacological or genetic inhibition of SOD1, we show that elevated intracellular superoxide (O-2(center dot-)) mediates sustained IKK phosphorylation, and induces downstream degradation of I kappa B alpha, leading to the nuclear localization and transcriptional activation of NF-kappa B. Mechanistically, we show that such sustained NF-kappa B signaling is a function of protein phosphatase 2A (PP2A) inactivation brought about by the nitrative modification of its substrate-binding sub-unit B56 gamma. Importantly, the pro-oxidant driven NF-kappa B activation enhances the migratory and invasive potential of cancer cells. In summary, our work highlights the critical involvement of O(2)(center dot-)dependent peroxynitrite production in inhibiting PP2A-mediated dephosphorylation of IKK, thereby facilitating cancers to acquire an invasive phenotype. Given that NF-kappa B is a key player of chronic inflammation and carcinogenesis, our work unravels a novel synergistic node involving O(2)(center dot-)driven redox milieu and deregulated PP2A as a potential therapeutic target.