scholarly journals Bortezomib induces canonical nuclear factor-κB activation in multiple myeloma cells

Blood ◽  
2009 ◽  
Vol 114 (5) ◽  
pp. 1046-1052 ◽  
Author(s):  
Teru Hideshima ◽  
Hiroshi Ikeda ◽  
Dharminder Chauhan ◽  
Yutaka Okawa ◽  
Noopur Raje ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Proteasome Inhibitors ◽  
Xenograft Model ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Down Regulation ◽  
Interacting Protein ◽  
Iκb Kinase

Bortezomib is a proteasome inhibitor with remarkable preclinical and clinical antitumor activity in multiple myeloma (MM) patients. The initial rationale for its use in MM was inhibition of nuclear factor (NF)-κB activity by blocking proteasomal degradation of inhibitor of κBα (IκBα). Bortezomib inhibits inducible NF-κB activity; however, its impact on constitutive NF-κB activity in MM cells has not yet been defined. In this study, we demonstrate that bortezomib significantly down-regulated IκBα expression and triggered NF-κB activation in MM cell lines and primary tumor cells from MM patients. Importantly, no inhibition of p65 (RelA) nuclear translocation was recognized after bortezomib treatment in a murine xenograft model bearing human MM cells. Bortezomib-induced NF-κB activation was mediated via the canonical pathway. Moreover, other classes of proteasome inhibitors also induced IκBα down-regulation associated with NF-κB activation. Molecular mechanisms whereby bortezomib induced IκBα down-regulation were further examined. Bortezomib triggered phosphorylation of IκB kinase (IKKβ) and its upstream receptor-interacting protein 2, whereas IKKβ inhibitor MLN120B blocked bortezomib-induced IκBα down-regulation and NF-κB activation, indicating receptor-interacting protein 2/IKKβ signaling plays crucial role in bortezomib-induced NF-κB activation. Moreover, IKKβ inhibitors enhanced bortezomib-induced cytotoxicity. Our studies therefore suggest that bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity in MM cells.

scholarly journals Biologic sequelae of IκB kinase (IKK) inhibition in multiple myeloma: therapeutic implications

Blood ◽  
2009 ◽  
Vol 113 (21) ◽  
pp. 5228-5236 ◽  
Author(s):  
Teru Hideshima ◽  
Dharminder Chauhan ◽  
Tanyel Kiziltepe ◽  
Hiroshi Ikeda ◽  
Yutaka Okawa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Nuclear Factor Κb ◽  
Down Regulation ◽  
Growth And Survival ◽  
Therapeutic Implications ◽  
Iκb Kinase ◽  
Canonical Pathways ◽  
Promising Treatment

Abstract Nuclear factor-κB (NF-κB) has an important role in multiple myeloma (MM) cell pathogenesis in the context of the bone marrow (BM) microenvironment. In NF-κB signaling cascades, IκB kinase α (IKKα) and IKKβ are key molecules that predominantly mediate noncanonical and canonical pathways, respectively. In this study, we examined the biologic sequelae of the inhibition of IKKα versus IKKβ in MM cell lines. All MM cell lines have constitutive canonical NF-κB activity, and a subset of MM cell lines shows noncanonical NF-κB activity. Adhesion to BM stromal cells further activates both canonical and noncanonical NF-κB activity. IKKβ inhibitor MLN120B blocks canonical pathway and growth of MM cell lines but does not inhibit the noncanonical NF-κB pathway. Although IKKα knockdown induces significant growth inhibition in the cell lines with both canonical and noncanonical pathways, it does not inhibit NF-κB activation. Importantly, IKKα down-regulation decreases expression of β-catenin and aurora-A, which are known to mediate MM cell growth and survival. Finally, IKKβ inhibitor enhances the growth inhibition triggered by IKKα down-regulation in MM cells with both canonical and noncanonical NF-κB activity. Combination therapy targeting these kinases therefore represents a promising treatment strategy in MM.

Proteasome Inhibitors Induce Inhibitory κB (IκB) Kinase Activation, IκBα Degradation, and Nuclear Factor κB Activation in HT-29 Cells

2004 ◽  
Vol 65 (2) ◽  
pp. 342-349 ◽  
Author(s):  
Zoltán H. Németh ◽  
Hector R. Wong ◽  
Kelli Odoms ◽  
Edwin A. Deitch ◽  
Csaba Szabó ◽  
...  
Keyword(s):  
Proteasome Inhibitors ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Kinase Activation ◽  
Iκb Kinase ◽  
Ht 29 ◽  
Iκbα Degradation

scholarly journals Mild Hypothermia Inhibits Nuclear Factor-κB Translocation in Experimental Stroke

2003 ◽  
Vol 23 (5) ◽  
pp. 589-598 ◽  
Author(s):  
Hyung Soo Han ◽  
Murat Karabiyikoglu ◽  
Stephen Kelly ◽  
Raymond A. Sobel ◽  
Midori A. Yenari
Keyword(s):  
Target Genes ◽  
Nuclear Translocation ◽  
Mild Hypothermia ◽  
Brain Temperature ◽  
Nuclear Factor Κb ◽  
Binding Activity ◽  
Cerebral Injury ◽  
Experimental Stroke ◽  
Nuclear Factor ◽  
Iκb Kinase

Nuclear factor-κB (NFκB) is a transcription factor that is activated after cerebral ischemia. NFκB activation leads to the expression of many inflammatory genes involved in the pathogenesis of stroke. The authors previously showed that mild hypothermia is protective even when cooling begins 2 h after stroke onset. In the present study, they examined the influence of hypothermia on NFκB activation. Rats underwent 2 h of transient middle cerebral artery occlusion. Brains were cooled to 33°C immediately after or 2 h after occlusion, and maintained for 2 h. After normothermic ischemia (brain temperature at 38°C), NFκB cytoplasmic expression, nuclear translocation, and binding activity were observed as early as 2 h in the ischemic hemisphere and persisted at 24 h. Hypothermia decreased NFκB translocation and binding activity but did not alter overall expression. Hypothermia also affected the levels of NFκB regulatory proteins by suppressing phosphorylation of NFκB's inhibitory protein (IκB-α) and IκB kinase (IKK-γ) and decreasing IKK activity, but did not alter overall IKK levels. Hypothermia suppressed the expression of two NFκB target genes: inducible nitric oxide synthase and TNF-α. These data suggest that the protective effect of hypothermia on cerebral injury is, in part, related to NFκB inhibition due to decreased activity of IKK.

scholarly journals The viral ankyrin repeat protein (ORF124L) from infectious spleen and kidney necrosis virus attenuates nuclear factor-κB activation and interacts with IκB kinase β

2011 ◽  
Vol 92 (7) ◽  
pp. 1561-1570 ◽  
Author(s):  
Chang-Jun Guo ◽  
Wei-Jian Chen ◽  
Li-Qun Yuan ◽  
Li-Shi Yang ◽  
Shao-Ping Weng ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Luciferase Reporter ◽  
Nuclear Factor ◽  
Mandarin Fish ◽  
Necrosis Virus ◽  
Necrosis Factor Alpha ◽  
Repeat Protein ◽  
Repeat Proteins ◽  
Iκb Kinase

The ankyrin (ANK) repeat is one of the most common protein–protein interaction motifs, found predominantly in eukaryotes and bacteria, but the functions of the ANK repeat are rarely researched in animal viruses, with the exception of poxviruses. Infectious spleen and kidney necrosis virus (ISKNV) is a typical member of the genus Megalocytivirus in the family Iridoviridae and is a causative agent of epizootics in fish. The genome of ISKNV contains four putative viral ANK (vANK) repeat proteins and their functions remain largely unknown. In the present study, it was found that ORF124L, a vANK repeat protein in ISKNV, encodes a protein of 274 aa with three ANK repeats. Transcription of ORF124L was detected at 12 h post-infection (p.i.) and reached a peak at 40 h p.i. ORF124L was found to localize to both the nucleus and the cytoplasm in mandarin fish fry cells. ISKNV ORF124L interacted with the mandarin fish IκB kinase β protein (scIKKβ), and attenuated tumour necrosis factor alpha (TNF-α)- or phorbol myristate acetate (PMA)-induced activity of a nuclear factor κB (NF-κB)–luciferase reporter but did not interfere with the activity of an activator protein 1 (AP-1)–luciferase reporter. Phosphorylation of IκBα and nuclear translocation of NF-κB were also impaired by ISKNV ORF124L. In summary, ORF124L was identified as a vANK repeat protein and its role in inhibition of TNF-α-induced NF-κB signalling was investigated through interaction with the mandarin fish IKKβ. This work may help to improve our understanding of the function of fish iridovirus ANK repeat proteins.

Testes-specific protease 50 (TSP50) promotes cell proliferation through the activation of the nuclear factor κB (NF-κB) signalling pathway

2011 ◽  
Vol 436 (2) ◽  
pp. 457-467 ◽  
Author(s):  
Zhen-Bo Song ◽  
Yong-Li Bao ◽  
Yu Zhang ◽  
Xu-Guang Mi ◽  
Ping Wu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Colony Formation ◽  
Nuclear Translocation ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Nuclear Factor Κb ◽  
Signalling Pathway ◽  
Nuclear Factor ◽  
Iκb Kinase ◽  
Specific Protease

TSP50 (testes-specific protease 50) is a testis-specific expression protein, which is expressed abnormally at high levels in breast cancer tissues. This makes it an attractive molecular marker and a potential target for diagnosis and therapy; however, the biological function of TSP50 is still unclear. In the present study, we show that overexpression of TSP50 in CHO (Chinese-hamster ovary) cells markedly increased cell proliferation and colony formation. Mechanistic studies have revealed that TSP50 can enhance the level of TNFα (tumour necrosis factor α)- and PMA-induced NF-κB (nuclear factor κB)-responsive reporter activity, IκB (inhibitor of NF-κB) α degradation and p65 nuclear translocation. In addition, the knockdown of endogenous TSP50 in MDA-MB-231 cells greatly inhibited NF-κB activity. Co-immunoprecipitation studies demonstrated an interaction of TSP50 with the NF-κB–IκBα complex, but not with the IKK (IκB kinase) α/β–IKKγ complex, which suggested that TSP50, as a novel type of protease, promoted the degradation of IκBα proteins by binding to the NF-κB–IκBα complex. Our results also revealed that TSP50 can enhance the expression of NF-κB target genes involved in cell proliferation. Furthermore, overexpression of a dominant-negative IκB mutant that is resistant to proteasome-mediated degradation significantly reversed TSP50-induced cell proliferation, colony formation and tumour formation in nude mice. Taken together, the results of the present study suggest that TSP50 promotes cell proliferation, at least partially, through activation of the NF-κB signalling pathway.

scholarly journals IKKα plays a major role in canonical NF-kB signalling in colorectal cells

2022 ◽  
Author(s):  
Jack A Prescott ◽  
Kathryn Balmanno ◽  
Jennifer P Mitchell ◽  
Hanneke Okkenhaug ◽  
Simon J Cook
Keyword(s):  
Cell Lines ◽  
Nuclear Translocation ◽  
Transcriptional Response ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Knock Out ◽  
Iκb Kinase ◽  
Sw620 Cells ◽  
Hct116 Cells

Inhibitor of kappa B (IκB) kinase β (IKKβ) has long been viewed as the dominant IKK in the canonical nuclear factor-κB (NF-κB) signalling pathway, with IKKα being more important in non-canonical NF-κB activation. Here we have investigated the role of IKKα and IKKβ in canonical NF-κB activation in colorectal cells using CRISPR-Cas9 knock-out cell lines, siRNA and selective IKKβ inhibitors. IKKα and IKKβ were redundant for IκBα phosphorylation and turnover since loss of IKKα or IKKβ alone had little (SW620 cells) or no (HCT116 cells) effect. However, in HCT116 cells IKKα was the dominant IKK required for basal phosphorylation of p65 at S536, stimulated phosphorylation of p65 at S468, nuclear translocation of p65 and the NF-κB-dependent transcriptional response to both TNFα and IL-1α. In these cells IKKβ was far less efficient at compensating for the loss of IKKα than IKKα was able to compensate for the loss of IKKβ. This was confirmed when siRNA was used to knock-down the non-targeted kinase in single KO cells. Critically, the selective IKKβ inhibitor BIX02514 confirmed these observations in WT cells and similar results were seen in SW620 cells. Notably, whilst IKKα loss strongly inhibited TNFα-dependent p65 nuclear translocation, IKKα and IKKβ contributed equally to c-Rel nuclear translocation indicating that different NF-κB subunits exhibit different dependencies on these IKKs. These results demonstrate a major role for IKKα in canonical NF-κB signalling in colorectal cells and may be relevant to efforts to design IKK inhibitors, which have focused largely on IKKβ to date.

Abstract 501: Nuclear Factor-κB Is Involved in Platelet CD40 Signaling and Activation

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Ahmed Hachem ◽  
Daniel Yacoub ◽  
Younes Zaid ◽  
Walid Mourad ◽  
Yahye Merhi
Keyword(s):  
P38 Mapk ◽  
Platelet Activation ◽  
Nuclear Translocation ◽  
Kinase Inhibitor ◽  
Tumor Necrosis Factor Receptor ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Nuclear Factor ◽  
Iκb Kinase ◽  
Iκbα Phosphorylation

Introduction and hypothesis: CD40 ligand (CD40L) is a thrombo-inflammatory molecule that predicts cardiovascular events. Platelets constitute the major source of soluble CD40L (sCD40L), which has been shown to influence platelet activation. We have previously shown that upon ligation, CD40 potentiates platelet activation and aggregation via p38 mitogen activated protein kinase (MAPK) and Rac1 signaling. In B lymphocytes, CD40 induces activation and nuclear translocation of nuclear factor kappa B (NF-κB), which is dependent on the phosphorylation and dissociation of the inhibitor of kappa B α (IκBα). Given that platelets contain NF-κB, we hypothesized that it may be involved in platelet CD40 signaling. Methods and results: In human platelets, sCD40L induced association of tumor necrosis factor receptor associated factor 2 to CD40, and a time-dependant phosphorylation of IκBα, which is indicative of NF-κB activation. Activation of NF-κB in platelets treated with sCD40L was abolished by CD40L blockade. Pretreatment of platelets with the IκBα inhibitor, BAY 11-7082, reversed IκBα phosphorylation induced by sCD40L, without affecting p38 MAPK activation. On the other hand, pretreatment of platelets with the p38 MAPK phosphorylation inhibitor, SB203580, had no effect on IκBα phosphorylation, indicating a divergence in the signaling pathway originating from CD40 upon its ligation. Finally, inhibition of IκBα phosphorylation by either BAY 11-7082 or the IκB kinase inhibitor VII reversed sCD40L induced platelet activation, as measured by P-selectin expression, and the potentiation of platelet aggregation induced by a priming dose of collagen. Conclusion: This study demonstrates the implication of NF-κB in platelet signaling downstream of CD40, where it plays a role in platelet activation and aggregation upon sCD40L stimulation.

scholarly journals Dehydroxymethylepoxyquinomicin, a Novel Nuclear Factor-κB Inhibitor, Enhances Antitumor Activity of Taxanes in Anaplastic Thyroid Cancer Cells

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5357-5365 ◽  
Author(s):  
Zhaowei Meng ◽  
Norisato Mitsutake ◽  
Masahiro Nakashima ◽  
Dmytro Starenki ◽  
Michiko Matsuse ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Nuclear Translocation ◽  
Combined Treatment ◽  
Xenograft Model ◽  
Anaplastic Thyroid Cancer ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Antitumor Activities

Nuclear factor κB (NF-κB), as an antiapoptotic factor, crucially affects the outcomes of cancer treatments, being one of the major culprits of resistance to chemotherapy. In this study, we investigated whether dehydroxymethylepoxyquinomicin (DHMEQ), a novel NF-κB inhibitor, can enhance antitumor activities of taxanes in anaplastic thyroid cancer (ATC) cells. Taxanes induced NF-κB activation in ATC cells, which could compromise the therapeutic effect of the drugs. However, DHMEQ, by inhibiting the nuclear translocation of NF-κB, completely suppressed the DNA binding capacities of NF-κB and lowered the levels of nuclear NF-κB protein. Compared with single treatment (either taxane or DHMEQ), the combined treatment strongly potentiated apoptosis, confirmed by cell survival assay; Western blotting for poly (ADP-ribose) polymerase, caspase 3, X-linked inhibitor of apoptosis, and survivin; and flow cytometry for annexin V. Furthermore, we also demonstrate for the first time that the combined treatment showed significantly greater inhibitory effect on tumor growth in a nude mice xenograft model. These findings suggest that taxanes are able to induce NF-κB activation in ATC cells, which could attenuate antitumor activities of the drugs, but inhibition of NF-κB by DHMEQ creates a chemosensitive environment and greatly enhances apoptosis in taxanes-treated ATC cells in vitro and in vivo. Thus, DHMEQ may emerge as an attractive therapeutic strategy to enhance the response to taxanes in ATCs.

scholarly journals The Protective Roles and Molecular Mechanisms of Troxerutin (Vitamin P4) for the Treatment of Chronic Diseases: A Mechanistic Review

2020 ◽  
Vol 19 (1) ◽  
pp. 97-110
Author(s):  
Mohammad Zamanian ◽  
Gholamreza Bazmandegan ◽  
Antoni Sureda ◽  
Eduardo Sobarzo-Sanchez ◽  
Hasan Yousefi-Manesh ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Therapeutic Potential ◽  
Acetylcholinesterase Activity ◽  
Nuclear Factor Κb ◽  
In Vivo Studies ◽  
Related Factor ◽  
Nuclear Factor

: Troxerutin (TRX), a semi-synthetic bioflavonoid derived from rutin, has been reported to exert several pharmacological effects including antioxidant, anti-inflammatory, antihyperlipidemic, and nephroprotective. However, the related molecular details and its mechanisms remain poorly understood. In the present review, we presented evidences from the diversity in vitro and in vivo studies on the therapeutic potential of TRX against neurodegenerative, diabetes, cancer and cardiovascular diseases with the purpose to find molecular pathways related to the treatment efficacy. TRX has a beneficial role in many diseases through multiple mechanisms including, increasing antioxidant enzymes and reducing oxidative damage, decreasing in proapoptotic proteins (APAF-1, BAX, caspases-9 and-3) and increasing the antiapoptotic BCL-2, increasing the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and downregulating the nuclear factor κB (NFκ). TRX also reduces acetylcholinesterase activity and upregulates phosphoinositide 3- kinase/Akt signaling pathway in Alzheimer’s disease models. Natural products such as TRX may develop numerous and intracellular pathways at several steps in the treatment of many diseases. Molecular mechanisms of action are revealing novel, possible combinational beneficial approaches to treat multiple pathological conditions.

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