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.

除了其在炎症和免疫中的生理作用外，核因子-κB（NF-κB）蛋白复合物还与肿瘤发生及其发展有关。在这里，我们提供证据表明，抗氧化剂环境是致癌性NF-κB信号传导的上游效应物。通过SOD1的药理学或基因抑制，我们表明，细胞内升高超氧（O ₂ ^-）介导IKK的持续磷酸化，并诱导IκBα的下游降解，从而导致NF-κB的核定位和转录激活。从机制上讲，我们显示这种持续的NF-κB信号是蛋白质磷酸酶2A（PP2A）失活的功能，该失活是由其底物结合亚基B56γ的硝化修饰引起的。重要的是，前氧化剂驱动的NF-κB活化增强了癌细胞的迁移和侵袭潜能。总而言之，我们的工作突出了O ₂的关键作用^-依赖性过氧亚硝酸盐的产生抑制PP2A介导的IKK的去磷酸化，从而促进癌症获得侵袭性表型。鉴于NF-κB是慢性炎症和癌症发生的关键球员，我们的工作揭开涉及新的协同节点Ø ₂ ^-驱动的氧化还原环境和放松管制的PP2A作为一个潜在的治疗靶点。