148 - Redox Dependent Activation of NF-kB Signaling in Cancer via Superoxide-Induced Phosphorylation of IKK

Abstract

Evidence over the years has highlighted the importance of intracellular redox status in determining cell fate. To date, our work has shown that a pro-oxidant intracellular milieu, particularly a mild increase in superoxide (O2•‒) promotes cancer cell survival and chemotherapeutic resistance. We previously demonstrated in vitro that elevated O2•‒, via silencing of superoxide dismutase (SOD1), resulted in sustained serine 70 phosphorylation of Bcl-2 which stabilizes its anti-apoptotic activity. These findings were corroborated by high serine 70 Bcl-2 phosphorylation and low SOD1 expression observed in primary clinical tumours obtained from patients with aggressive lymphomas and/or disease with poor prognosis. Besides anti-apoptotic Bcl-2, a master pro-inflammatory transcription factor, nuclear factor kappa B (NF-κB) was also shown to be modulated by intracellular redox milieu. As constitutive NF-κB activation is reported in various human tumours and is often associated with malignant progression and chemoresistance, it is pertinent to investigate whether a pro-oxidant environment, specifically the upregulation of intracellular O2•‒, was associated with induction of NF-κB transcriptional activity. Indeed, we demonstrate that elevated intracellular O2•‒ resulting from pharmacological inhibition or genetic silencing of SOD1 leads to enhanced canonical NF-κB signalling. This is accompanied by increased p65 nuclear localization and transcription of NF-κB regulated genes, which potentially confer survival advantages to tumour cells upon chemotherapeutic treatments. Considering the association between NF-κB activation, chronic inflammation and the process of carcinogenesis, these preliminary data provide a novel mechanism of activation of this master transcriptional factor with potential therapeutic implications.