IκBα targeting promotes oxidative stress-dependent cell death

BACKGROUND: Oxidative stress is a hallmark of many cancers. The increment in reactive oxygen species (ROS), resulting from an increased mitochondrial respiration, is the major cause of oxidative stress. Cell fate is known to be intricately linked to the amount of ROS produced. The direct generation of ROS is also one of the mechanisms exploited by common anticancer therapies, such as chemotherapy.METHODS: We assessed the role of NFKBIA with various approaches, including in silico analyses, RNA-silencing and xenotransplantation. Western blot analyses, immunohistochemistry and RT-qPCR were used to detect the expression of specific proteins and genes. Immunoprecipitation and pull-down experiments were used to evaluate protein-protein interactions.RESULTS: Here, by using an in silico approach, following the identification of NFKBIA (the gene encoding IkappaBalpha) amplification in various cancers, we described an inverse correlation between IkappaBalpha, oxidative metabolism, and ROS production in lung cancer. Furthermore, we showed that novel IkappaBalpha targeting compounds combined with cisplatin treatment promote an increase in ROS beyond the tolerated threshold, thus causing death by oxytosis.CONCLUSIONS: NFKBIA amplification and IkappaBalpha overexpression identify a unique cancer subtype associated with specific expression profile and metabolic signatures. Through p65-NFKB regulation, IkappaBalpha overexpression favors metabolic rewiring of cancer cells and distinct susceptibility to cisplatin. Lastly, we have developed a novel approach to disrupt IkappaBalpha/p65 interaction, restoring p65-mediated apoptotic responses to cisplatin due to mitochondria deregulation and ROS-production.