Section 3.2.4: NF-kappaB signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)
From publication: "Targeting cancer stem cell pathways for cancer therapy" published as Signal Transduct Target Ther; 2020 ; 5 8; DOI: https://doi.org/10.1038/s41392-020-0110-5
Section 3.2.4: NF-kappaB signaling pathway in CSCs
Nuclear factor-kappaB (NF-kappaB), a rapidly inducible transcription factor, consists of five different proteins (p65, RelB, c-Rel, NF-kappaB1, and NF-kappaB2). The main physiological function of NF-kappaB is the p50-p65 dimer. The primary mode of NF-kappaB regulation occurs at the level of subcellular localization. In the activation stage, transcription factor complexes must translocate from the cytoplasm to the nucleus. The activity of the complexes is regulated by two major pathways (canonical NF-kappaB signaling and noncanonical NF-kappaB signaling). In the canonical NF-kappaB activation pathway, activation occurs through the binding of ligands, such as bacterial cell components, IL-1beta, TNF-alpha, or lipopolysaccharides, to their respective receptors, such as Toll-like receptors, TNF receptor (TNFR), IL-1 receptor (IL-1R), and antigen receptors. Stimulation of these receptors leads to the phosphorylation and activation of IkappaB kinase (IKK) proteins, subsequently initiating the phosphorylation of IkappaB proteins. The alternative pathway of NF-kappaB activation is termed the noncanonical pathway. The noncanonical pathway receptor originates from different classes, such as CD40, receptor activator for NF-kappaB, B cell activation factor, TNFR2 and Fn14, and lymphotoxin beta-receptor. This pathway leads to activation of NF-kappaB by inducing the kinase (NIK), which then phosphorylates and predominantly activates IKK1. The activity of the latter enzyme induces the phosphorylation of p100 to generate p52.
Figure 3: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005297/bin/41392_2020_110_Fig3_HTML.jpg
Figure 3 caption: The NF-kappaB pathway plays an important role in regulating immune and inflammatory responses. In addition, the NF-kappaB pathway is involved in cellular survival, proliferation, and differentiation. The process of tumor development and progression produces cytokines, growth, and angiogenic factors and proteases to activate NF-kappaB signaling. Inflammation has been recognized as a hallmark of cancer. Overactivation of NF-kappaB signaling has been reported in gastrointestinal, genitourinary, gynecological, and head and neck cancers, breast tumors, multiple myeloma, and blood cancers. However, direct or altered molecular mutations in NF-kappaB have rarely been reported in human cancers. Based on recent studies, NF-kappaB regulates many genes and is implicated in cell survival, proliferation, metastasis, and tumorigenesis of cancer. NF-kappaB activation also directly or indirectly enhances the expression of key angiogenesis factors and adhesion molecules, such as IL-8, vascular endothelial growth factor (VEGF), and growth-regulated oncogene 1.
NF-kappaB signaling pathway in cancer stem cells NF-kappaB proteins are involved in the dimerization of transcription factors, regulate gene expression, and affect various CSC biological processes, including inflammation, stress responses, growth, and development of CSCs. The main physiological function of NF-kappaB is the p50-p65 dimer. The active p50-p65 dimer is further activated by post-translational modification (phosphorylation, acetylation, or glycosylation) and transported into the nucleus, which induces the expression of target genes in combination with other transcription factors. Some proteins (CD44, CD146, TNFRSF19, Bmi-1, FOXP3, and SDF-1) and microRNAs (miR-221 and miR-222) directly regulate the NF-kappaB pathway. In addition, some proteins (PGE2, GIT-1 (G protein-coupled receptor kinase-interacting protein 1), C-C chemokine receptor 7 (CCR7), and TGF-beta) and miR-491 indirectly affect the NF-kappaB pathway via the ERK and MAPK pathways in CSCs
The NF-kappaB pathway has an essential connection regulating inflammation, self-renewal, or maintenance and metastasis of CSCs (Fig. 3). CD44+ cells promote self-renewal, metastasis, and maintenance of ovarian CSCs by increasing the expression of RelA, RelB, and IKKalpha and mediating nuclear activation of p50/RelA (p50/p65) dimer. High levels of NIK induce activation of the noncanonical NF-kappaB pathway to regulate the self-renewal and metastasis of breast CSCs. Moreover, stromal cell-derived factor-1 (SDF-1) also has the same effect by regulating the translocation of p65 from the cytoplasm to the nucleus. The inflammatory mediator prostaglandin E2 (PGE2) contributes to tumor formation, maintenance, and metastasis by activating NF-kappaB via EP4-PI3K (phosphoinositide 3-kinase) and EP4-MAPK pathways in colorectal CSCs. Chemokines, low-molecular-weight proinflammatory cytokines, are important mediators of cell proliferation, metastasis, and apoptosis. C-C chemokine receptor 7 interacts with its ligand chemokine ligand 21 to inhibit apoptosis and induce survival and migration in CD133+ pancreatic cancer stem-like cells by increasing the expression of extracellular signal-regulated kinase 1/2 (Erk1/2) and p65. Furthermore, B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) also enhances the p65 protein in gastric CSCs. MicroRNAs also play an important role in promoting the proliferation of CSCs. Mir-221/222 promotes self-renewal, migration, and invasion in breast CSCs by inhibiting the expression of PTEN and then inducing the phosphorylation of AKT, resulting in elevated p65, p-p65, and COX2.
In addition, other transcription factors also inhibit self-renewal and metastasis in CSCs by the NF-kappaB pathway. Increased expression of FOXP3 has been identified in different cancers. FOXP3 interacts with NF-kappaB, inhibits the expression of COX2 located downstream of NF-kappaB, and affects self-renewal and metastasis in colorectal CSCs. Overexpression of miR-491 blocks the activation of NF-kappaB in liver CSCs by targeting G protein-coupled receptor kinase-interacting protein 1, which inhibits ERKs. Moreover, some drugs inhibit cell proliferation and metastasis of CSCs by the NF-kappaB pathway. Disulfiram, an anti-alcoholism drug, inhibits tumor growth factor-beta (TGF-beta)-induced metastasis via the ERK/NF-kappaB/Snail pathway in breast CSCs. Sulforaphane preferentially inhibits self-renewal in triple-negative breast CSCs by inhibiting NF-kappaB p65 subunit translocation and downregulating p52 and its transcriptional activity. Curcumin regulates the proliferation, metastasis, and apoptosis of HCC stem cells by inhibiting the NF-kappaB pathway. These data demonstrate that amplified NF-kappaB signaling is important for regulating apoptosis, proliferation, and metastasis of CSCs.
