Abstract
The nuclear factor kappa B (NF-κB) is a ubiquitous transcription factor central to inflammation and various malignant diseases in humans. The regulation of NF-κB can be influenced by a myriad of post-translational modifications (PTMs), including phosphorylation, one of the most popular PTM formats in NF-κB signaling. The regulation by phosphorylation modification is not limited to NF-κB subunits, but it also encompasses the diverse regulators of NF-κB signaling. The differential site-specific phosphorylation of NF-κB itself or some NF-κB regulators can result in dysregulated NF-κB signaling, often culminating in events that induce cancer progression and other hyper NF-κB related diseases, such as inflammation, cardiovascular diseases, diabetes, as well as neurodegenerative diseases, etc. In this review, we discuss the regulatory role of phosphorylation in NF-κB signaling and the mechanisms through which they aid cancer progression. Additionally, we highlight some of the known and novel NF-κB regulators that are frequently subjected to phosphorylation. Finally, we provide some future perspectives in terms of drug development to target kinases that regulate NF-κB signaling for cancer therapeutic purposes.
Highlights
The evidence for the role of nuclear factor κB (NF-κB) in the promotion of cell survival pathways in various cancers continues to accumulate over the years
NF-κB is key to the inflammation, metastasis, angiogenesis, immune evasion, and metabolic reprograming observed in numerous cancers
NF-κB-dependent gene transcription is tightly regulated by distinct post-translational modifications (PTMs), such as phosphorylation
Summary
Cancer is a diverse and multifactorial genetic disease that arises through a multistep accumulation of genetic alterations, which causes genomic instability in a cell. KRAS oncogenic mutation and p53 loss of function mutation, which is present in approximately 25% and 50% of human tumors, respectively, leads to the constitutive activation of NF-κB, thereby promoting cell survival in multiple cancers. Mutations in the PI-3-Kinase/Akt pathway, which exist in over 30% of solid tumors, promotes the activation of components in NF-κB pathway [2,5]. These examples, among many others, demonstrate the complex signaling interactions in cancer and the Biomolecules 2021, 11, 15. We will further elaborate on the complexity of NF-κB regulation in cancer, with the goal of providing deep insight and aiding the development strategies of novel NF-κB targeted cancer therapeutics
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