Subunit-Specific Role of NF-κB in Cancer

Kaltschmidt, Barbara; Greiner, Johannes F. W.; Kadhim, Hussamadin M.; Kaltschmidt, Christian

doi:10.3390/biomedicines6020044

Cited by 91 publications

(82 citation statements)

References 76 publications

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“…Transcription factor NF-κB, which is expressed ubiquitously in the cytoplasm, has been discovered in 1986 and has since been found to be the major regulator of inflammation and tumorigenesis. The constitutive activation of p65-NF-κB (RELA), especially, plays a pivotal role in solid cancers [60]. Phosphorylation of the p65-NF-κB subunit by IKKs/IκBα is a major activation step in the canonical NF-κB pathway, followed by nuclear translocation and DNA binding to modulate gene transcription [61].…”

Section: Discussionmentioning

confidence: 99%

Evidence That Calebin A, a Component of Curcuma Longa Suppresses NF-κB Mediated Proliferation, Invasion and Metastasis of Human Colorectal Cancer Induced by TNF-β (Lymphotoxin)

et al. 2019

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Objective: Natural polyphenol Calebin A has been recently discovered as a novel derivate from turmeric with anti-cancer potential. Pro-inflammatory cytokine TNF-β (lymphotoxin α) is a stimulant for cancer cell malignity via activation of NF-κB pathway, also in colorectal cancer (CRC). Here, we investigated the potential of Calebin A to suppress TNF-β-induced NF-κB signalling in CRC. Materials and Methods: Three distinct CRC cell lines (HCT116, RKO, SW480) were treated in monolayer or 3-dimensional alginate culture with TNF-β, Calebin A, curcumin, BMS-345541, dithiothreitol (DTT) or antisense oligonucleotides-(ASO) against NF-κB. Results: Calebin A suppressed dose-dependent TNF-β-induced CRC cell vitality and proliferation in monolayer culture. Further, in alginate culture, Calebin A significantly suppressed TNF-β-enhanced colonosphere development, as well as invasion and colony formation of all three CRC cell lines investigated. Calebin A specifically blocked TNF-β-induced activation and nuclear translocation of p65-NF-κB, similar to curcumin (natural NF-κB inhibitor), BMS-345541 (specific IKK inhibitor) and ASO-NF-κB. Moreover, Immunofluorescence and Immunoblotting showed that Calebin A, similar to curcumin or BMS-345541 suppressed TNF-β-induced activation and nuclear translocation of p65-NF-κB and the transcription of NF-κB-promoted biomarkers associated with proliferation, migration and apoptosis, in a doseand time-dependent manner. Those findings were potentiated by the specific treatment of extracted nuclei with DTT, which abrogated Calebin A-mediated nuclear p65-NF-κB-inhibition and restored p65-NF-κB-activity in the nucleus. Conclusion: Overall, these results demonstrate, for the first time, that multitargeted Calebin A has an anti-cancer capability on TNF-β-induced malignities through inhibitory targeting of NF-κB activation in the cytoplasm, as well as by suppressing the binding of p65-NF-κB to DNA.

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Section: Discussionmentioning

confidence: 99%

Evidence That Calebin A, a Component of Curcuma Longa Suppresses NF-κB Mediated Proliferation, Invasion and Metastasis of Human Colorectal Cancer Induced by TNF-β (Lymphotoxin)

et al. 2019

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“…While there are common factors known to regulate both pathways in cancer cells to support tumorigenesis, such as IKKα, in general there is limited information about how the two pathways may overlap in ovarian cancer or in other cancer cell types. By contrast, there is stronger evidence showing that each pathway can individually influence cancer cell behavior and promote tumorigenesis across the spectrum from borderline tumors to invasive carcinomas, dependent on factors such as tumor type, localization, and microenvironment [ 43 , 55 , 56 ].…”

Section: Discussionmentioning

confidence: 99%

Expression of p52, a non-canonical NF-kappaB transcription factor, is associated with poor ovarian cancer prognosis

et al. 2020

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Background The canonical and non-canonical nuclear factor-kappaB (NF-κB) signaling pathways have key roles in cancer, but studies have previously evaluated only the association of canonical transcription factors and ovarian cancer survival. Although a number of in vitro and in vivo studies have demonstrated mechanisms by which non-canonical NF-κB signaling potentially contributes to ovarian cancer progression, a prognostic association has yet to be shown in the clinical context. Methods We assayed p65 and p52 (major components of the canonical and non-canonical NF-κB pathways) by immunohistochemistry in epithelial ovarian tumor samples; nuclear and cytoplasmic staining were semi-quantified by H-scores and dichotomized at median values. Associations of p65 and p52 with progression-free survival (PFS) and overall survival (OS) were quantified by Hazard Ratios (HR) from proportional-hazards regression. Results Among 196 cases, median p52 and p65 H-scores were higher in high-grade serous cancers. Multivariable regression models indicated that higher p52 was associated with higher hazards of disease progression (cytoplasmic HR: 1.54; nuclear HR: 1.67) and death (cytoplasmic HR: 1.53; nuclear HR: 1.49), while higher nuclear p65 was associated with only a higher hazard of disease progression (HR: 1.40) in unadjusted models. When cytoplasmic and nuclear staining were combined, p52 remained significantly associated with increased hazards of disease progression (HR: 1.91, p = 0.004) and death (HR: 1.70, p = 0.021), even after adjustment for p65 and in analyses among only high-grade serous tumors. Conclusions This is the first study to demonstrate that p52, a major component of non-canonical NF-κB signaling, may be an independent prognostic factor for epithelial ovarian cancer, particularly high-grade serous ovarian cancer. Approaches to inhibit non-canonical NF-κB signaling should be explored as novel ovarian cancer therapies are needed.

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“…In addition, oxymatrine upregulated E-cadhern expression and downregulated SNAI2 and vimentin expression, indicating that oxymatrine reverse the EMT phenotype of HCT-8/5-FU cells. The activation of the NF-κB signaling pathway is important for the regulation of cell proliferation, differentiation, survival, migration, invasion and the EMT process (40)(41)(42). The NF-κB signaling pathway is involved in transforming growth factor β-induced EMT and the 5-Fu chemotherapy resistance in colon cancer (43,44).…”

Section: Discussionmentioning

confidence: 99%

Oxymatrine reverses 5‑fluorouracil resistance by inhibition of colon cancer cell epithelial‑mesenchymal transition and NF‑κB signaling in�vitro

Liang

Luo

et al. 2019

Oncol Lett

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The present study investigated the sensitization of 5-fluorouracil (5-FU)-resistant colon cancer cells in vitro, using oxymatrine, a Chinese herb, and a quinolizidine alkaloid compound extracted from the root of Sophora flavescens. The HCT-8 colon cancer cell line and its 5-FU-resistant subline HCT-8/5-FU were treated with 5-FU and oxymatrine, alone or in combination, at various doses. The cells were subsequently assessed for changes in cell viability, apoptosis and morphology and analyzed by fluorescence microscopy and western blotting. The data demonstrated that HCT-8/5-FU markedly increased the dose of 5-FU required for the suppression of tumor cell viability (78.77±1.90 µg/ml vs. 9.20±0.96 µg/ml in parental HCT-8 cells), whereas HCT-8/5-FU induced the tumor cell epithelial-mesenchymal transition (EMT). By contrast, oxymatrine alone and in combination with 5-FU altered HCT-8/5-FU cell morphology, apoptosis and EMT phenotypes. The combination of oxymatrine and 5-FU reduced the protein expression of snail family transcriptional repressor 2 and vimentin, phosphorylated p65 and induced the expression of E-cadherin, by inhibiting the nuclear factor κB (NF-κB) signaling pathway. In conclusion, the data from the present study demonstrated that EMT was associated with 5-FU chemoresistance in HCT-8/5-FU colon cancer cells, and that oxymatrine treatment was able to reverse such resistance. Oxymatrine may regulate tumor cell EMT and inactivate the NF-κB signaling pathway, and may therefore serve as a potential therapeutic drug to reverse 5-FU resistance in colon cancer cells.

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Subunit-Specific Role of NF-κB in Cancer

Cited by 91 publications

References 76 publications

Evidence That Calebin A, a Component of Curcuma Longa Suppresses NF-κB Mediated Proliferation, Invasion and Metastasis of Human Colorectal Cancer Induced by TNF-β (Lymphotoxin)

Evidence That Calebin A, a Component of Curcuma Longa Suppresses NF-κB Mediated Proliferation, Invasion and Metastasis of Human Colorectal Cancer Induced by TNF-β (Lymphotoxin)

Expression of p52, a non-canonical NF-kappaB transcription factor, is associated with poor ovarian cancer prognosis

Oxymatrine reverses 5‑fluorouracil resistance by inhibition of colon cancer cell epithelial‑mesenchymal transition and NF‑κB signaling in�vitro

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