IκBα targeting promotes oxidative stress-dependent cell death

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

Genomic characterization of thymic epithelial tumors reveals critical genes underlying tumorigenesis and poor prognosis

“…Moreover, NFKBIA has been suggested as a potential target for small molecules such as antioxidants to suppress NF‐κB activation 40 . Through p65‐NFKB regulation, IκBα overexpression favors metabolic rewiring of cancer cells and distinct susceptibility to cisplatin 41 . By increasing IkB‐α levels, it was found NFKBIA can be targeted by proteasome inhibitors in DLBCL, as well as by bromodomain and extraterminal protein (BET) inhibitors 38 .…”

Shedding Light on NF-κB Functions in Cellular Organelles

“…This amplification correlates not only with impaired mitochondrial metabolism, but also with lower chemosensitivity. Pharmacological or genetic approaches targeting IκBα induce oxidative metabolism and promote an increase in ROS level beyond the tolerated threshold, causing stress-dependent cell death ( Carra et al, 2021 ). It has been demonstrated that hypoxia-stimuli induce a transient and rapid accumulation of RelA/IκBα complex into mitochondria in a STAT3-dependent manner.…”

“…Cancer cells increase their aerobic metabolism and reduce mitochondrial activity to aid their sustenance, a mechanism known as Warburg effect ( Vander Heiden et al, 2009 ). In this respect, we have shown that IκBα down-modulation and therefore NF-κB activation in lung cancer cells, induces a mitochondrial unbalancing toward β-oxidation and an up-regulation of several key lipid metabolism genes, and in turn increases mitochondrial respiration ( Carra et al, 2021 ). Accordingly, Mauro et al identified NF-κB/RelA as a physiological regulator of mitochondrial respiration.…”

“…These pharmacological approaches provide a link between ER stress and NF-κB although their mechanisms and specificity need to be further evaluated. Concerning the targeting NF-κB with respect to its activity in the different cellular compartments, we demonstrated that targeting or silencing IκBα with PSA in the IκBα-overespressing lung cancer cells, significantly induce mitochondria OXPHOS and increased ROS content and release, correlating with a significant increased sensitivity to apoptotic cell death ( Carra et al, 2021 ). Moreover, it has been demonstrated that IκBα knock-down sensitizes cells to apoptosis and reduces tumor burden in a cancer mouse model.…”

NF-κB-Dependent and -Independent (Moonlighting) IκBα Functions in Differentiation and Cancer

“…In agreement with this observation, high levels of IκBα predicts a therapeutic response in patients treated with EGFR inhibitors [ 54 ]. In contrast, compound targeting IκBα enhanced the susceptibility of lung cancer cells to cisplatin, leading to reactive oxygen species (ROS)-induced cell death [ 55 ].…”