Sustained IKKβ phosphorylation and NF-κB activation by superoxide-induced peroxynitrite-mediated nitrotyrosine modification of B56γ3 and PP2A inactivation

Apart from its physiological role in inflammation and immunity, the nuclear factor-kappa B (NF-κB) 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-κB signaling. Through pharmacological or genetic inhibition of SOD1, we show that elevated intracellular superoxide (O2·-) mediates sustained IKK phosphorylation, and induces downstream degradation of IκBα, leading to the nuclear localization and transcriptional activation of NF-κB. Mechanistically, we show that such sustained NF-κB signaling is a function of protein phosphatase 2A (PP2A) inactivation brought about by the nitrative modification of its substrate-binding sub-unit B56γ. Importantly, the pro-oxidant driven NF-κB activation enhances the migratory and invasive potential of cancer cells. In summary, our work highlights the critical involvement of O2·--dependent peroxynitrite production in inhibiting PP2A-mediated dephosphorylation of IKK, thereby facilitating cancers to acquire an invasive phenotype. Given that NF-κB is a key player of chronic inflammation and carcinogenesis, our work unravels a novel synergistic node involving O2·--driven redox milieu and deregulated PP2A as a potential therapeutic target.