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Nuclear Factor Kappa-B: Bridging Inflammation and Cancer
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Mohammad Aslam Khan, Girijesh Kumar Patel, Haseeb Zubair, Nikhil Tyagi, Shafquat Azim, Seema Singh, Aamir Ahmad, Ajay Pratap Singh
NF-κB transcriptionally regulates expression of genes which are involved in cell survival, apoptosis, differentiation and immune responses [42, 43]. As discussed above, NF-κB family consists of five members. Both the precursors (NF-κB1/p105 and NF-κB2/ p100) contain IκB-homologous regions at the C-terminal that function as NF-κB inhibitors. Proteolytic processing removes inhibitory domains, allowing the processed proteins (NF-κB1/ p50 and NF-κB2/p52) to enter into the nucleus. Inside the nucleus, p50 and p52 form homodimers or heterodimers with Rel family proteins [42]. All these NF-κB associated proteins have Rel homology domain (RHD) at the N-terminal region. Some of the NF-κB proteins (p65, c-Rel and RelB) contain transcriptional activation domain (TAD) at C-terminal, and these TAD containing proteins positively regulate transcriptional activity. On the other hand, two TAD lacking proteins, p52 and p100, negatively regulate gene expression when bound as homodimer, but can activate gene expression when recruited with other TAD containing proteins like p65. RelB and cRel [44]. Activation of NF-κB pathway is either by classical/canonical or the alternate/non-canonical signaling pathways.
Dendritic Cells Control the Balance between Tolerance and Autoimmunity
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Simon W. F. Milling, G. Gordon MacPherson
T cells pass through the thymus as they develop. Thymocytes express a diverse repertoire of different T cell receptor-encoded specificities for MHC/peptide molecules. To prevent autoimmunity, it is crucial that the majority of self-reactive T cells are deleted; this occurs through a process called “negative selection” which occurs in the medulla of the thymus and appears to be mediated by dendritic cells. Thymic epithelial cells express a key transcription factor called AIRE (autoimmune regulator) that promotes ectopic expression of antigens normally restricted to peripheral tissues.47 Dendritic cells are crucial for negative selection as they are thought to cross-present such antigens,48 causing deletion of self-reactive thymocytes and the establishment of a safe repertoire of peripheral T cells. In fact, autoimmune CD4+ T cells comprise up to 5% of the peripheral repertoire in relB-/-mice, which lack CD8α- and the majority of their functional CD8α+ DCs.49
Nutraceutical’s Role in Proliferation and Prevention of Gynecological Cancers
Published in Sheeba Varghese Gupta, Yashwant V. Pathak, Advances in Nutraceutical Applications in Cancer, 2019
Aaishwarya B. Deshmukh, Jayvadan K. Patel, Bharat Mishra
NF-κB as a nuclear factor was found to bind to the enhancer element of the immunoglobulin kappa light chain of activated B cells (hence abbreviated NF-κB) [41]. The five members of NF-κB group of proteins identified are RelB, p65 (RelA), NF-κB1 (p105/p50), NF-κB2 (p100/p52), and c-Rel [42–45]. The expression of genes involved in the various processes of transformation and development of tumor cells is regulated by the transcription factor NF-κB by various proinflammatory stimuli such as TNF-α, lipopolysaccharide, IL-1b, and oxidative stress, which induce expression of multiple genes encoding proinflammatory cytokines, growth and angiogenic factors, chemokines adhesion molecules, such as ICAM-1 and e-selectin VCAM-1, and inducible enzymes like iNOS and COX-2 [46]. The apprehension that the c-rel, which is a cellular homologue of the oncogene v-rel, encodes for a NF-κB subunit and binds to the same DNA binding domain has given the first proof of link between NF-κB and cancer [47]. In addition, the detection of active NF-κB in cancer tissues of the patients, including those with lymphoma and leukemia and cancers of breast, prostate, pancreas, oral cavity, colon, liver, and ovary support the link between NF-κB and cancer [48]. All these point to the relevance or importance of NF-κB pathway in cancer, and so this pathway has been manifested as a favored target for therapeutic development.
Oral administration of Bifidobacterium breve promotes antitumor efficacy via dendritic cells-derived interleukin 12
Published in OncoImmunology, 2021
Qingxiang Li, Yuke Li, Yifei Wang, Le Xu, Yuxing Guo, Yixiang Wang, Lin Wang, Chuanbin Guo
As the most powerful and professional antigen-presenting cells (APC), DCs’ main function is to process and present antigen to T cells. To better understand DCs’ changes derived from B. breve’s stimulation, the expression level of APC response-related genes was evaluated by qRT-PCR. The expression of Relb, which was one of the most primary transcription factors associated with DC development and maturation was upregulated (Figure 4(a)). Il-12a and Il-12b genes encoded the subunits of IL-12, a bridge cytokine that connected DCs and T cells, were significantly upregulated (approximately 10 times) after B. breve’s treatment (Figure 4(b)). Antigen processing related genes, Rab27a, Slc11a1 and Tapbp, were also upregulated in B. breve group (Figure 4(c)). It was remarkable that vital co-stimulatory molecules, especially CD40 and CD70, were upregulated due to B. breve intervention (Figure 4(d)). Some crucial genes in type I interferon signaling also exhibited upregulation (Figure 4(e)). Then apart from these, expression of Th1-type chemokines CX3CL1 and CXCL9 also increased in B. breve group (Figure 4(f)). Compared with control group, L. rhamnosus treatment didn’t exhibit significant promotion effect on BMDC maturation. But E. coli group showed similar results as B. breve group. In summary, direct stimulation of B. breve was able to induce BMDC to become mature and prime the antigen processing-related genes and signaling.
Bladder neoplasms and NF-κB: an unfathomed association
Published in Expert Review of Molecular Diagnostics, 2020
Charles Emmanuel Jebaraj Walter, Sankari Durairajan, Kalaiselvi Periyandavan, George Priya Doss C, Dicky John Davis G, Hannah Rachel Vasanthi A, Thanka Johnson, Hatem Zayed
NF-κB is activated by upstream lymphotoxin β receptor (LTβR) in chronic cystitis and potentiates its progression to bladder cancer [59,60]. LTβR belongs to the tumor necrosis factor (TNF) receptor superfamily expressed on epithelial cells and most other cells [21]. LTβR signaling is involved in inflammatory processes and carcinogenesis, especially inflammation-induced carcinogenesis [61,62]. Astudy assessing chronic cystitis, bladder cancer and healthy mucosa tissues showed that along with LTβR, both NF-κB:canonical RelA and non-canonical RelB were expressed at higher levels in chronic cystitis and bladder cancer than in healthy bladder mucosa. In addition, the alternate pathway protein RelB predominantly potentiates the transition from bladder inflammation to cancer. The study concluded that there was no significance between age or gender and the expression of LTβR, RelA and RelB [21]. Thus, chronic cystitis exhibiting active NF-κB pathways might lead to bladder cancer via inflammation-associated proteins like LTβR.
Modulating multidrug resistance to drug-based antitumor therapies through NF-κB signaling pathway: mechanisms and perspectives
Published in Expert Opinion on Therapeutic Targets, 2023
Dapeng Wu, Sai Tian, Wenjing Zhu
NF-κB is a crucial regulator of various biological processes, including proliferation, apoptosis, angiogenesis, and invasion. The IκB kinase IKKα in the NF-κB signaling pathway, in conjunction with ERα, could promote the proliferation of breast cancer by activating the transcription of estrogen-responsive genes c-myc and cyclin D1 [122]. Studies have shown the NF-κB pathway activation is both the effect and cause of inflammation within the breast tumor microenvironment and inflammation contributes to the aggressive phenotypes of ER+ breast cancer [123]. The tamoxifen‐resistant cells usually display active NF‐κB signaling, and the combination of tamoxifen and NF‐κB inhibitor ACT001 could significantly inhibit the growth of tamoxifen‐resistant cells [124]. It has also been demonstrated that NF‐κB upregulation contributes to endocrine resistance of the antiestrogen Faslodex, and NF-κB inhibitor Parthenolide could restore Faslodex-induced apoptosis and restore tamoxifen sensitivity in antiestrogen-resistant breast cancer cells [125]. In ER-positive breast cancers, the absolute expression level of ER correlates positively with the responsiveness of the tumor to tamoxifen treatment. Inhibition of NF-κB could enhance ERa expression in a dose-dependent manner, reducing the resistance of resistant breast cancer tumor cells to tamoxifen [126]. In the non-canonical NF-κB pathway, the NF-κB subunit RelB could enhance the expression of B-lymphocyte-induced maturation protein (BLIMP1) which could repress ER transcription by binding to the ER promoter region [127]. RelB was demonstrated to sustain endocrine resistant malignancy in breast cancer, suggesting the non-canonical NF-κB pathway is also involved in resistance against endocrine therapy [128].