Sustained IKKß 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.

The anti-oxidant and pro-oxidant dichotomy of Bcl-2.

Across a wide spectrum of cellular redox status, there emerges a dichotomy of responses in terms of cell survival/proliferation and cell death. Of note, there is emerging evidence that the anti-apoptotic protein, Bcl-2, in addition to its conventional activity of titrating the pro-apoptotic effects of proteins such as Bax and Bak at the mitochondria, also impacts cell fate decisions via modulating cellular redox metabolism. In this regard, both pro- and anti-oxidant effects of Bcl-2 overexpression have been described under different conditions and cellular contexts. In this short review, we attempt to analyze existing observations and present a probable explanation for the seemingly conflicting redox regulating activity of Bcl-2 from the standpoint of its pro-survival function. The consequential effect(s) of the dual redox functions of Bcl-2 are also discussed, particularly from the viewpoint of developing novel therapeutic strategies against cancers rendered refractory due to the aberrant expression of Bcl-2.