NF-kB SIGNALING PATHWAY

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The persistent activation of NF-kB has been linked with tumor development. Indeed, this transcription factor can support cell transformation, tumor cell survival, proliferation, invasion, metastatization and neoangiogenesis (29). NF-kB is a homodimeric or heterodimeric transcription factor which can be formed by different combinations of five subunits (RelA/p65, c-Rel, RelB, NF-kB1/p50, and NF-kB2/p52). This transcription factor is ordinarily sequestered in an inactive state in the cytoplasm by the inhibitors of NF-kBs (IkBs). Activation of the IkB kinase (IKK) complex, which includes two catalytic (IKKα and IKKβ) and one regulatory (IKKγ/NEMO) subunit, leads to phosphorylation of the IkBs, targeting them for ubiquitination and proteasomal degradation. The degradation of IkBs permits NF-kB to translocate to the nucleus, where it activates different genes involved in inflammation, cell growth, cell survival and invasivity (30). Indeed, the activation of NF-kB represents a critical link between inflammation and tumorigenesis and is triggered by growth factors, cytokines and many stress stimuli (29-31). The constant activation of NF-kB in cancer cells is supported by the high levels of inflammatory mediators (tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, prostaglandin E2 (PGE2) and reactive oxygen species) within the tumor microenvironment (24,29-32).

Cyclooxygenases (COX-1 and COX-2), are key enzymes responsible for the biosynthesis of prostaglandins (PGs) and thromboxanes (TXs) from arachidonic acid. These enzymes and their products play a key role in inflammation and tumor progression (33). COX-2 expression is highly induced by growth factors, proinflammatory cytokines and other tumor promoters and its activity is dysregulated in several types of cancer (33). In addition, COX-2-derived PGE2 is the principal prostaglandin found in human tumors and it promotes tumor progression by inducing cell proliferation, migration, invasion, angiogenesis and by inhibiting apoptosis (33). Conversely, COX-1 is constitutively expressed (33). COX-2 expression is mainly controlled by NF-kB, AP-1 and their upstream kinases, MAPKs (33). In addition, to attain its full biological activity, NF-kB must undergo different post-translational modifications, including acetylation. Acetylation at different lysine residues in the RelA/p65 subunit affects definite functions of NF-kB, including transcriptional activation, DNA binding, and assembly with its inhibitor IkB (34,35). NF-kB acetylation is accomplished by different histone acetyltransferases (HATs) (34,35). NF-kB canonical signaling pathway is illustrated in Figure 1, panel B.