The Direct and Indirect Roles of NF-κB in Cancer: Lessons from Oncogenic Fusion Proteins and Knock-in Mice

Abstract

NF-κB signaling pathways play an important role in the regulation of cellular immune and stress responses. Aberrant NF-κB activity has been implicated in almost all the steps of cancer development and many of the direct and indirect contributions of this transcription factor system for oncogenesis were revealed in the recent years. The indirect contributions affect almost all hallmarks and enabling characteristics of cancer, but NF-κB can either promote or antagonize these tumor-supportive functions, thus prohibiting global NF-κB inhibition. The direct effects are due to mutations of members of the NF-κB system itself. These mutations typically occur in upstream components that lead to the activation of NF-κB together with further oncogenesis-promoting signaling pathways. In contrast, mutations of the downstream components, such as the DNA-binding subunits, contribute to oncogenic transformation by affecting NF-κB-driven transcriptional output programs. Here, we discuss the features of recently identified oncogenic RelA fusion proteins and the characterization of pathways that are regulating the transcriptional activity of NF-κB by regulatory phosphorylations. As NF-κB’s central role in human physiology prohibits its global inhibition, these auxiliary or cell type-specific NF-κB regulating pathways are potential therapeutic targets.

The levels of NF-κB p50 and NF-κB p65 play a role in thyroid carcinoma malignancy in vivo

“… 12 In addition, NF-κB is also involved in the response of cells to stimuli such as free radicals, ultraviolet radiation, cytokines, bacterial or viral antigens; and it plays a key role in regulating the immune system's response to infection. 13 , 14 At present, NF-κB is considered to be uncontrolled and associated with malignancy, inflammation, viral infections, septic shock and other types of diseases. 4 , 5 NF-κB family members have five subunits in humans: Rel, RelB, p50, p52 and p65.…”

NF-κB Signaling in Targeting Tumor Cells by Oncolytic Viruses—Therapeutic Perspectives

“…NF-κB controls epithelial-mesenchymal transition and the expression of cell adhesion molecules (CAMs), such as E-selectin, intracellular CAM (ICAM)-1, vascular CAM (VCAM)-1, and integrins [ 14 , 17 ]. However, inhibition of NF-κB may not be beneficial for anticancer therapy since angiogenesis is antagonized by NF-κB.…”

“…The role of NF-κB in replicative immortality involves upregulation of the telomerase catalytic subunit (TERT)-encoding gene, whereas the expression of NF-κB-dependent genes is regulated by TERT [ 17 ]. Also, genetic instability can be acquired via the DNA damage induced by oxidative stress, which activates NF-κB [ 2 , 17 ]. NF-κB’s direct role in cancer is based on the mutations of NF-κB regulatory proteins.…”

“…NF-κB’s direct role in cancer is based on the mutations of NF-κB regulatory proteins. Mostly, gain-of-function mutations of upstream NF-κB activators are responsible for NF-κB-driven cancers [ 2 , 4 , 17 ]. In addition, genetic and chromosomal alterations of NF-KB1 , NF-KB2 , and REL are typical for a variety of types of blood cancers [ 2 , 17 ].…”

Biochemical aspects of the combined use of taxanes, irradiation and other antineoplastic agents for the treatment of anaplastic thyroid carcinoma

“…Dysregulation of NFκB functions leads to inflammation and is associated with serious disea ses, including cancer [52,57]. NFκB is constitutively active in most types of cancer, and many signaling pathways involved in carcinogenesis are accompanied by this factor activation [54,58]. The possible participation of the chronic inflammation in carcinogenesis of thyroid glands is based on the observation that chronic autoimmune thyroiditis (AIT) is often accompanied by the malignant transformation of thyroid tissue [59].…”