IκB[alpha] targeting promotes oxidative stress-dependent cell death.

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Publisher: BioMed Central Ltd.
Document Type: Article
Length: 8,296 words
Lexile Measure: 1420L

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Abstract :

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 IκB[alpha]) amplification in various cancers, we described an inverse correlation between IκB[alpha], oxidative metabolism, and ROS production in lung cancer. Furthermore, we showed that novel IκB[alpha] targeting compounds combined with cisplatin treatment promote an increase in ROS beyond the tolerated threshold, thus causing death by oxytosis. Conclusions NFKBIA amplification and IκB[alpha] overexpression identify a unique cancer subtype associated with specific expression profile and metabolic signatures. Through p65-NFKB regulation, IκB[alpha] overexpression favors metabolic rewiring of cancer cells and distinct susceptibility to cisplatin. Lastly, we have developed a novel approach to disrupt IκB[alpha]/p65 interaction, restoring p65-mediated apoptotic responses to cisplatin due to mitochondria deregulation and ROS-production. Keywords: NFKBIA, OXPHOS, Oxidative stress, Programmed cell death, Oxytosis, IκB[alpha]

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Gale Document Number: GALE|A661455026