IKBKB

Gene Summary

Gene:IKBKB; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta
Aliases: IKK2, IKKB, IMD15, NFKBIKB, IKK-beta
Location:8p11.2
Summary:The protein encoded by this gene phosphorylates the inhibitor in the inhibitor/NF-kappa-B complex, causing dissociation of the inhibitor and activation of NF-kappa-B. The encoded protein itself is found in a complex of proteins. Several transcript variants, some protein-coding and some not, have been found for this gene. [provided by RefSeq, Sep 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:inhibitor of nuclear factor kappa-B kinase subunit beta
HPRD
Source:NCBIAccessed: 08 August, 2015

Ontology:

What does this gene/protein do?
Show (42)
Pathways:What pathways are this gene/protein implicaed in?
Show (23)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 08 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Phosphorylation
  • Thyroid Cancer
  • Transcription Factor RelB
  • Substrate Specificity
  • mRNA Cleavage and Polyadenylation Factors
  • Skin Cancer
  • Thiophenes
  • Prostate Cancer
  • Software
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • IKBKB
  • RNA Interference
  • Transcription Factor RelA
  • Apoptosis
  • Neoplasms, Experimental
  • siRNA
  • Statistics, Nonparametric
  • Tumor Stem Cell Assay
  • Transfection
  • TNF
  • I-kappa B Kinase
  • p38 Mitogen-Activated Protein Kinases
  • Sulfones
  • X-Linked Combined Immunodeficiency Diseases
  • Two-Hybrid System Techniques
  • Vesicular stomatitis Indiana virus
  • Translocation
  • Cancer Gene Expression Regulation
  • Splenic Neoplasms
  • Sulfasalazine
  • Ubiquitins
  • RNA-Binding Proteins
  • Kaposi Sarcoma
  • NF-kappa B
  • Salicylic Acid
  • Promoter Regions
  • Tobacco
  • Chromosome 8
  • rac1 GTP-Binding Protein
  • T-Lymphocytes
  • Ubiquitination
Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: IKBKB (cancer-related)

Kadioglu O, Nass J, Saeed ME, et al.
Kaempferol Is an Anti-Inflammatory Compound with Activity towards NF-κB Pathway Proteins.
Anticancer Res. 2015; 35(5):2645-50 [PubMed] Related Publications
BACKGROUND: The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway is critical in inflammation, proliferation and carcinogenesis. There exist three main players in this pathway. The inhibitor of NF-κB (IκB), IκB kinase (IκK)- NF-κB essential modulator (NEMO) complex and NF-κB. The IkK-NEMO complex activates NF-κB via phosphorylation of Iκβ and, eventually, leads to its proteasomal degradation. This leads to nuclear translocation of NF-κB and activation of target genes, such as cyclooxygenases and interleukins. The identification of anti-inflammatory compounds might be an effective strategy to target inflammatory disorders and cancer.
MATERIALS AND METHODS: In the present investigation, kaempferol was investigated in terms of its effect on NF-κB activity with a SEAP-driven reporter cell line, NF-κB DNA binding with electromobility shift assay (EMSA) and translocation of NF-κB-p65 from cytosol to the nucleus with western blot in Jurkat cells.
RESULTS: Kaempferol revealed anti-inflammatory activity, as shown in vitro and in silico. Molecular docking studies of kaempferol revealed comparable binding energies and similar docking poses on target proteins such as MG-132, a known NF-κB inhibitor.
CONCLUSION: We conclude that kaempferol possesses anti-inflammatory activity.

Tian Y, Hao S, Ye M, et al.
MicroRNAs let-7b/i suppress human glioma cell invasion and migration by targeting IKBKE directly.
Biochem Biophys Res Commun. 2015; 458(2):307-12 [PubMed] Related Publications
We demonstrated that IKBKE is overexpressed in human gliomas and that the downregulation of IKBKE markedly inhibits the proliferative and invasive abilities of glioma cells, which is consistent with the results reported by several different research groups. Therefore, IKBKE represents a promising therapeutic target for the treatment of glioma. In the present study, we verified that the microRNAs let-7b and let-7i target IKBKE through luciferase assays and found that let-7b/i mimics can knock down IKBKE and upregulate E-cadherin through western blot analysis. Moreover, the expression levels of let-7b/i were significantly lower in glioma cell lines than that in normal brain tissues, as determined by quantitative real-time PCR. Furthermore, let-7b/i inhibit the invasion and migration of glioma cells, as determined through wound healing and Transwell assays. The above-mentioned data suggest that let-7b/i inhibit the invasive ability of glioma cells by directly downregulating IKBKE and indirectly upregulating E-cadherin.

Abdel-Latif MM, Kelleher D, Reynolds JV
Molecular mechanisms of constitutive and inducible NF-kappaB activation in oesophageal adenocarcinoma.
Eur J Cancer. 2015; 51(4):464-72 [PubMed] Related Publications
BACKGROUND: Nuclear factor-kappaB (NF-κB) regulates the expression of a large number of genes involved in the immune and inflammatory response. NF-κB is constitutively activated in oesophageal tumour tissues and induced in oesophageal cells by bile and acid. The aim of the present study was to define the mechanisms underlying NF-κB activation in oesophageal adenocarcinoma.
PATIENTS AND METHODS: Fresh biopsy specimens were obtained from 20 patients with oesophageal adenocarcinoma. The activation of NF-κB in oesophageal tumour specimens and oesophageal SKGT-4 cells was assessed by gel mobility shift and Western blotting. Phosphorylation of protein kinase B (AKT/PKB), Ikappa kinase-alpha/beta (IKK-α/β) and extracellular signal-regulated kinase 1/2 (ERK1/2) was examined by Western blotting. High content analysis was used to quantify NF-κB translocation in oesophageal cells.
RESULTS: Oesophageal tumour tissues had higher levels of NF-κB. Increased levels of phosphorylated AKT and IKK-α/β and ERK1/2 were detected in tumour tissues compared with normal oesophageal mucosa. Exposure of SKGT-4 cells to deoxycholic acid (DCA) or acid resulted in NF-κB activation and phosphorylation of AKT, IKK-α/β and ERK1/2. Specific inhibitors for phosphoinositide 3-kinase; PI3K (LY294002 and worhmannin) and ERK1/2 inhibitors (PD98059 and U0126) suppressed DCA- and acid-induced NF-κB activation. The proteasome inhibitor MG-132 and the antioxidants vitamin C and pyrrolidine dithiocarbamate (PDTC) also inhibited NF-κB activation.
CONCLUSIONS: Our data demonstrate a major role for PI3K/AKT-IKK-α/β-ERK1/2 signalling pathway in NF-κB activation in oesophageal adenocarcinoma. These results suggest that NF-κB may be a prognostic marker for oesophageal adenocarcinoma, and modulating of NF-κB may uncover new therapeutic strategies.

Zhao L, Zhang Y
miR-342-3p affects hepatocellular carcinoma cell proliferation via regulating NF-κB pathway.
Biochem Biophys Res Commun. 2015; 457(3):370-7 [PubMed] Related Publications
Recent research indicates that non-coding microRNAs (miRNAs) help regulate basic cellular processes in many types of cancer cells. We hypothesized that overexpression of miR-342-3p might affect proliferation of hepatocellular carcinoma (HCC) cells. After confirming overexpression of miR-342-3p with qRT-PCR, MTT assay showed that HCC cell proliferation was significantly inhibited by miR-342-3p, and that it significantly decreased BrdU-positive cell proliferation by nearly sixfold. Searching for targets using three algorithms we found that miR-342-3p is related to the NF-κB pathway and luciferase assay found that IKK-γ, TAB2 and TAB3 are miR-342-3p target genes. Results of western blot on extracted nuclear proteins of HepG2 and HCT-116 cells showed that miR-342-3p reduced and miR-342-3p-in increased p65 nuclear levels and qRT-PCR found that NF-κB pathway downstream genes were downregulated by miR-342-3p and upregulated by miR-342-3p-in, confirming that miR-342 targets NF-κB pathway. Overexpression of Ikk-γ, TAB2 and TAB3 partially rescued HCC cells proliferation inhibited by miR-342-3p. Using the GSE54751 database we evaluated expression from 10 HCC samples, which strongly suggested downregulation of miR-342-3p and we also found inverse expression between miR-342-3p and its targets IKK-γ, TAB2 and TAB3 from 71 HCC samples. Our results show that miR-342-3p has a significant role in HCC cell proliferation and is suitable for investigation of therapeutic targets.

Verstrepen L, Beyaert R
Receptor proximal kinases in NF-κB signaling as potential therapeutic targets in cancer and inflammation.
Biochem Pharmacol. 2014; 92(4):519-29 [PubMed] Related Publications
Many signaling pathways leading to activation of transcription factors and gene expression are characterized by phosphorylation events mediated by specific kinases. The transcription factor NF-κB plays a key role in multiple cellular processes, including immune signaling, inflammation, development, proliferation and survival. Dysregulated NF-κB activation is associated with autoimmunity, chronic inflammation and cancer. Activation of NF-κB requires IκB kinase (IKK)α or β, the activity of which is regulated via phosphorylation by specific IKK kinases and by autophosphorylation. Receptor specificity is further obtained by the use of multiple upstream receptor proximal kinases. We review the identities of several IKK regulatory kinases as well as the proposed molecular mechanisms. In addition, we discuss the potential for therapeutic targeting of some of these kinases in the context of inflammatory diseases and cancer.

Nagasawa T, Matsushima-Nishiwaki R, Yasuda E, et al.
Heat shock protein 20 (HSPB6) regulates TNF-α-induced intracellular signaling pathway in human hepatocellular carcinoma cells.
Arch Biochem Biophys. 2015; 565:1-8 [PubMed] Related Publications
We previously demonstrated that the expression of HSP20, a small heat shock protein, is inversely correlated with the progression of HCC. Inflammation is associated with HCC, and numerous cytokines, including TNF-α, act as key mediators in the progression of HCC. In the present study, we investigated whether HSP20 is implicated in the TNF-α-stimulated intracellular signaling in HCC using human HCC-derived HuH7 cells in the presence of TNF-α. In HSP20-overexpressing HCC cells, the cell growth was retarded compared with that in the control cells under long-term exposure of TNF-α. Because NF-κB pathway is the main intracellular signaling system activated by TNF-α, we investigated the effects of HSP20-overexpression of this pathway. The protein levels of IKK-α, but not IKK-β, in the HSP20-overexpressing cells were decreased. Short-term exposure to TNF-α-induced phosphorylation and degradation of IκB, and the phosphorylation and transactivational activity of NF-κB were suppressed in the HSP20-overexpressing HCC cells. Furthermore, the increase in IKK-α levels was accompanied by a decrease in the HSP20 levels in human HCC tissues. These findings strongly suggest that HSP20 might decrease the IKK-α protein level and that it down-regulates the TNF-α-stimulated intracellular signaling in HCC, thus resulting in the suppression of HCC progression.

Dou A, Wang Z, Zhao J, et al.
Identification of therapeutic target genes with DNA microarray in multiple myeloma cell line treated by IKKβ/NF-κB inhibitor.
Acta Cir Bras. 2014; 29(11):696-702 [PubMed] Related Publications
PURPOSE: To explore the mechanism of resistance to IKKβ inhibitor in multiple myeloma (MM) cells and uncover novel therapeutic targets for MM.
METHODS: We downloaded the microarray data (GSE8476) from GEO (Gene Expression Omnibus) database. The data were derived from the human MM cells lines (L363 cells) treated with IKKβ inhibitor MLN120b (MLN) for eight, 12 and 24 hours. Furthermore, we applied the Search Tool for the Retrieval of Interacting Genes (STRING) and Expression Analysis Systematic Explorer (EASE) database to construct protein-protein interaction networks and identified over-represented pathway among DEGs (differentially expressed genes).
RESULTS: We obtained 108 DGEs in 8h vs. 12h group and 101 ones in 8h vs. 24h group. Most of DGEs were found to be involved in biological regulation. The significant pathways were Ig A pathway and the CAMs pathways. In addition, 24 common DGEs were found in the networks of the two groups such as ICAM 3 and SELL.
CONCLUSION: Intercellular adhesion molecule 3 and SELL may be potential targets in multiple myeloma treatment in the future.

Zhu YX, Yin H, Bruins LA, et al.
RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2.
Blood. 2015; 125(3):483-91 [PubMed] Free Access to Full Article Related Publications
To identify molecular targets that modify sensitivity to lenalidomide, we measured proliferation in multiple myeloma (MM) cells transfected with 27 968 small interfering RNAs in the presence of increasing concentrations of drug and identified 63 genes that enhance activity of lenalidomide upon silencing. Ribosomal protein S6 kinase (RPS6KA3 or RSK2) was the most potent sensitizer. Other notable gene targets included 5 RAB family members, 3 potassium channel proteins, and 2 peroxisome family members. Single genes of interest included I-κ-B kinase-α (CHUK), and a phosphorylation dependent transcription factor (CREB1), which associate with RSK2 to regulate several signaling pathways. RSK2 knockdown induced cytotoxicity across a panel of MM cell lines and consistently increased sensitivity to lenalidomide. Accordingly, 3 small molecular inhibitors of RSK2 demonstrated synergy with lenalidomide cytotoxicity in MM cells even in the presence of stromal contact. Both RSK2 knockdown and small molecule inhibition downregulate interferon regulatory factor 4 and MYC, and provides an explanation for the synergy between lenalidomide and RSK2 inhibition. Interestingly, RSK2 inhibition also sensitized MM cells to bortezomib, melphalan, and dexamethasone, but did not downregulate Ikaros or influence lenalidomide-mediated downregulation of tumor necrosis factor-α or increase lenalidomide-induced IL-2 upregulation. In summary, inhibition of RSK2 may prove a broadly useful adjunct to MM therapy.

Yang J, Hawkins OE, Barham W, et al.
Myeloid IKKβ promotes antitumor immunity by modulating CCL11 and the innate immune response.
Cancer Res. 2014; 74(24):7274-84 [PubMed] Free Access to Full Article Related Publications
Myeloid cells are capable of promoting or eradicating tumor cells and the nodal functions that contribute to their different roles are still obscure. Here, we show that mice with myeloid-specific genetic loss of the NF-κB pathway regulatory kinase IKKβ exhibit more rapid growth of cutaneous and lung melanoma tumors. In a BRAF(V600E/PTEN(-/-)) allograft model, IKKβ loss in macrophages reduced recruitment of myeloid cells into the tumor, lowered expression of MHC class II molecules, and enhanced production of the chemokine CCL11, thereby negatively regulating dendritic-cell maturation. Elevated serum and tissue levels of CCL11 mediated suppression of dendritic-cell differentiation/maturation within the tumor microenvironment, skewing it toward a Th2 immune response and impairing CD8(+) T cell-mediated tumor cell lysis. Depleting macrophages or CD8(+) T cells in mice with wild-type IKKβ myeloid cells enhanced tumor growth, where the myeloid cell response was used to mediate antitumor immunity against melanoma tumors (with less dependency on a CD8(+) T-cell response). In contrast, myeloid cells deficient in IKKβ were compromised in tumor cell lysis, based on their reduced ability to phagocytize and digest tumor cells. Thus, mice with continuous IKKβ signaling in myeloid-lineage cells (IKKβ(CA)) exhibited enhanced antitumor immunity and reduced melanoma outgrowth. Collectively, our results illuminate new mechanisms through which NF-κB signaling in myeloid cells promotes innate tumor surveillance.

Campa VM, Baltziskueta E, Bengoa-Vergniory N, et al.
A screen for transcription factor targets of glycogen synthase kinase-3 highlights an inverse correlation of NFκB and androgen receptor signaling in prostate cancer.
Oncotarget. 2014; 5(18):8173-87 [PubMed] Free Access to Full Article Related Publications
Expression of Glycogen Synthase Kinase-3 (GSK-3) is elevated in prostate cancer and its inhibition reduces prostate cancer cell proliferation, in part by reducing androgen receptor (AR) signaling. However, GSK-3 inhibition can also activate signals that promote cell proliferation and survival, which may preclude the use of GSK-3 inhibitors in the clinic. To identify such signals in prostate cancer, we screened for changes in transcription factor target DNA binding activity in GSK-3-silenced cells. Among the alterations was a reduction in AR DNA target binding, as predicted from previous studies, and an increase in NFκB DNA target binding. Consistent with the latter, gene silencing of GSK-3 or inhibition using the GSK-3 inhibitor CHIR99021 increased basal NFκB transcriptional activity. Activation of NFκB was accompanied by an increase in the level of the NFκB family member RelB. Conversely, silencing RelB reduced activation of NFκB by CHIR99021. Furthermore, the reduction of prostate cancer cell proliferation by CHIR99021 was potentiated by inhibition of NFκB signaling using the IKK inhibitor PS1145. Finally, stratification of human prostate tumor gene expression data for GSK3 revealed an inverse correlation between NFκB-dependent and androgen-dependent gene expression, consistent with the results from the transcription factor target DNA binding screen. In addition, there was a correlation between expression of androgen-repressed NFκB target genes and reduced survival of patients with metastatic prostate cancer. These findings highlight an association between GSK-3/AR and NFκB signaling and its potential clinical importance in metastatic prostate cancer.

Iannetti A, Ledoux AC, Tudhope SJ, et al.
Regulation of p53 and Rb links the alternative NF-κB pathway to EZH2 expression and cell senescence.
PLoS Genet. 2014; 10(9):e1004642 [PubMed] Free Access to Full Article Related Publications
There are two major pathways leading to induction of NF-κB subunits. The classical (or canonical) pathway typically leads to the induction of RelA or c-Rel containing complexes, and involves the degradation of IκBα in a manner dependent on IκB kinase (IKK) β and the IKK regulatory subunit NEMO. The alternative (or non-canonical) pathway, involves the inducible processing of p100 to p52, leading to the induction of NF-κB2(p52)/RelB containing complexes, and is dependent on IKKα and NF-κB inducing kinase (NIK). Here we demonstrate that in primary human fibroblasts, the alternative NF-κB pathway subunits NF-κB2 and RelB have multiple, but distinct, effects on the expression of key regulators of the cell cycle, reactive oxygen species (ROS) generation and protein stability. Specifically, following siRNA knockdown, quantitative PCR, western blot analyses and chromatin immunoprecipitation (ChIP) show that NF-κB2 regulates the expression of CDK4 and CDK6, while RelB, through the regulation of genes such as PSMA5 and ANAPC1, regulates the stability of p21WAF1 and the tumour suppressor p53. These combine to regulate the activity of the retinoblastoma protein, Rb, leading to induction of polycomb protein EZH2 expression. Moreover, our ChIP analysis demonstrates that EZH2 is also a direct NF-κB target gene. Microarray analysis revealed that in fibroblasts, EZH2 antagonizes a subset of p53 target genes previously associated with the senescent cell phenotype, including DEK and RacGAP1. We show that this pathway provides the major route of crosstalk between the alternative NF-κB pathway and p53, a consequence of which is to suppress cell senescence. Importantly, we find that activation of NF-κB also induces EZH2 expression in CD40L stimulated cells from Chronic Lymphocytic Leukemia patients. We therefore propose that this pathway provides a mechanism through which microenvironment induced NF-κB can inhibit tumor suppressor function and promote tumorigenesis.

Yokoigawa J, Morimoto K, Shiono Y, et al.
Allantopyrone A, an α-pyrone metabolite from an endophytic fungus, inhibits the tumor necrosis factor α-induced nuclear factor κB signaling pathway.
J Antibiot (Tokyo). 2015; 68(2):71-5 [PubMed] Related Publications
Tumor necrosis factor α (TNF-α) induces the activation of transcription factor nuclear factor κB (NF-κB), which upregulates a variety of genes, including the gene encoding intercellular adhesion molecule-1 (ICAM-1). Allantopyrone A, a recently identified α-pyrone metabolite from an endophytic fungus, was found to inhibit the TNF-α-induced expression of ICAM-1 in human lung carcinoma A549 cells. Allantopyrone A also inhibited the TNF-α-induced luciferase expression of an NF-κB-responsive reporter. In the NF-κB signaling pathway, allantopyrone A inhibited the nuclear translocation of NF-κB subunits as well as the phosphorylation and subsequent degradation of the inhibitor of NF-κB (IκB) α proteins. By contrast, allantopyrone A did not directly affect the catalytic activity of active IκB kinase β. These findings indicate that allantopyrone A inhibits the NF-κB signaling pathway at a step upstream of IκBα phosphorylation.

Kai X, Chellappa V, Donado C, et al.
IκB kinase β (IKBKB) mutations in lymphomas that constitutively activate canonical nuclear factor κB (NFκB) signaling.
J Biol Chem. 2014; 289(39):26960-72 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
Somatic mutations altering lysine 171 of the IKBKB gene that encodes (IKKβ), the critical activating kinase in canonical (NFκB) signaling, have been described in splenic marginal zone lymphomas and multiple myeloma. Lysine 171 forms part of a cationic pocket that interacts with the activation loop phosphate in the activated wild type kinase. We show here that K171E IKKβ and K171T IKKβ represent kinases that are constitutively active even in the absence of activation loop phosphorylation. Predictive modeling and biochemical studies establish why mutations in a positively charged residue in the cationic pocket of an activation loop phosphorylation-dependent kinase result in constitutive activation. Transcription activator-like effector nuclease-based knock-in mutagenesis provides evidence from a B lymphoid context that K171E IKKβ contributes to lymphomagenesis.

Park SH, Lee JH, Berek JS, Hu MC
Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53.
Int J Oncol. 2014; 45(4):1691-8 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
Auranofin is a gold-containing compound classified by the World Health Organization as a clinically established rheumatoid arthritis therapeutic agent. Through drug screening for novel anticancer therapeutics, we unexpectedly identified auranofin as a potent anticancer agent against a p53-null ovarian carcinoma SKOV3 cell line. However, the molecular mechanism underlying auranofin-mediated anticancer activity in ovarian cancer cells is basically unknown. Here, we show that auranofin inhibits proliferation and survival of SKOV3 cells in a dose‑ and time‑dependent manner. Auranofin treatment activates the pro-apoptotic caspase-3, increases protein levels of apoptosis-inducing proteins Bax and Bim and reduces the expression of the anti-apoptotic mediator Bcl-2 in SKOV3 cells. Moreover, auranofin downregulates IκB kinase (IKK)-β and promotes nuclear localization and the activation of FOXO3 tumor suppressor, leading to cellular apoptosis in SKOV3 cells. In contrast, silencing FOXO3 diminishes the pro-apoptotic signaling of auranofin in SKOV3 cells. These results suggest that auranofin may induce caspase-3-mediated apoptosis in a FOXO3-dependent manner. The observed upregulation of pro-apoptotic genes and apoptosis in cancer cells without p53 in response to auranofin suggests a novel p53-independent mechanism underlying auranofin-induced apoptosis in ovarian cancer cells.

Han JG, Gupta SC, Prasad S, Aggarwal BB
Piperlongumine chemosensitizes tumor cells through interaction with cysteine 179 of IκBα kinase, leading to suppression of NF-κB-regulated gene products.
Mol Cancer Ther. 2014; 13(10):2422-35 [PubMed] Related Publications
Recently, two different reports appeared in prominent journals suggesting a mechanism by which piperlongumine, a pyridine alkaloid, mediates anticancer effects. In the current report, we describe another novel mechanism by which this alkaloid mediates its anticancer effects. We found that piperlongumine blocked NF-κB activated by TNFα and various other cancer promoters. This downregulation was accompanied by inhibition of phosphorylation and degradation of IκBα. Further investigation revealed that this pyridine alkaloid directly interacts with IκBα kinase (IKK) and inhibits its activity. Inhibition of IKK occurred through interaction with its cysteine 179 as the mutation of this residue to alanine abolished the activity of piperlongumine. Inhibition in NF-κB activity downregulated the expression of proteins involved in cell survival (Bcl-2, Bcl-xL, c-IAP-1, c-IAP-2, survivin), proliferation (c-Myc, cyclin D1), inflammation (COX-2, IL6), and invasion (ICAM-1, -9, CXCR-4, VEGF). Overall, our results reveal a novel mechanism by which piperlongumine can exhibit antitumor activity through downmodulation of proinflammatory pathway.

Linnewiel-Hermoni K, Motro Y, Miller Y, et al.
Carotenoid derivatives inhibit nuclear factor kappa B activity in bone and cancer cells by targeting key thiol groups.
Free Radic Biol Med. 2014; 75:105-20 [PubMed] Related Publications
Aberrant activation of the nuclear factor kappa B (NFkB) transcription system contributes to cancer progression, and has a harmful effect on bone health. Several major components of the NFkB pathway such as IkB Kinase (IKK) and the NFkB subunits contain cysteine residues that are critical for their activity. The interaction of electrophiles with these cysteine residues results in NFkB inhibition. Carotenoids, hydrophobic plant pigments, are devoid of electrophilic groups, and we have previously demonstrated that carotenoid derivatives, but not the native compounds activate the Nrf2 transcription system. The aim of the current study was to examine whether carotenoid derivatives inhibit NFkB, and, if so, to determine the molecular mechanism underpinning the inhibitory action. We report in the present study that a mixture of oxidized derivatives, prepared by ethanol extraction from partially oxidized lycopene preparation, inhibited NFkB reporter gene activity. In contrast, the intact carotenoid was inactive. A series of synthetic dialdehyde carotenoid derivatives inhibited reporter activity as well as several stages of the NFkB pathway in both cancer and bone cells. The activity of the carotenoid derivatives depended on the reactivity of the electrophilic groups in reactions such as Michael addition to sulfhydryl groups of proteins. Specifically, carotenoid derivatives directly interacted with two key proteins of the NFkB pathway: the IKKβ and the p65 subunit. Direct interaction with IKKβ was found in an in vitro kinase assay with a recombinant enzyme. The inhibition by carotenoid derivatives of p65 transcriptional activity was observed in a reporter gene assay performed in the presence of excess p65. This inhibition action resulted, at least in part, from direct interaction of the carotenoid derivative with p65 leading to reduced binding of the protein to DNA as evidenced by electrophoretic mobility shift assay (EMSA) experiments. Importantly, we found by using mutation in key cysteine residues of both p65 and IKK that specific thiol groups are essential for NFkB inhibition by carotenoid derivatives. In conclusion, we propose that electrophilic carotenoid derivatives contribute to cancer prevention as well as bone health maintenance via the inhibition of the NFkB transcription system. Pivotal thiol groups of both IKK and p65 play a key role in this process.

Kaldenbach M, Cubero FJ, Erschfeld S, et al.
Hepatic tissue environment in NEMO-deficient mice critically regulates positive selection of donor cells after hepatocyte transplantation.
PLoS One. 2014; 9(6):e100786 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
BACKGROUND: Hepatocyte transplantation (HT) is a promising alternative treatment strategy for end-stage liver diseases compared with orthotopic liver transplantation. A limitation for this approach is the low engraftment of donor cells. The deletion of the I-kappa B kinase-regulatory subunit IKKγ/NEMO in hepatocytes prevents nuclear factor (NF)-kB activation and triggers spontaneous liver apoptosis, chronic hepatitis and the development of liver fibrosis and hepatocellular carcinoma. We hypothesized that NEMOΔhepa mice may therefore serve as an experimental model to study HT.
METHODS: Pre-conditioned NEMOΔhepa mice were transplanted with donor-hepatocytes from wildtype (WT) and mice deficient for the pro-apoptotic mediator Caspase-8 (Casp8Δhepa).
RESULTS: Transplantation of isolated WT-hepatocytes into pre-conditioned NEMOΔhepa mice resulted in a 6-7 fold increase of donor cells 12 weeks after HT, while WT-recipients showed no liver repopulation. The use of apoptosis-resistant Casp8Δhepa-derived donor cells further enhanced the selection 3-fold after 12-weeks and up to 10-fold increase after 52 weeks compared with WT donors. While analysis of NEMOΔhepa mice revealed strong liver injury, HT-recipient NEMOΔhepa mice showed improved liver morphology and decrease in serum transaminases. Concomitant with these findings, the histological examination elicited an improved liver tissue architecture associated with significantly lower levels of apoptosis, decreased proliferation and a lesser amount of liver fibrogenesis. Altogether, our data clearly support the therapeutic benefit of the HT procedure into NEMOΔhepa mice.
CONCLUSION: This study demonstrates the feasibility of the NEMOΔhepa mouse as an in vivo tool to study liver repopulation after HT. The improvement of the characteristic phenotype of chronic liver injury in NEMOΔhepa mice after HT suggests the therapeutic potential of HT in liver diseases with a chronic inflammatory phenotype and opens a new door for the applicability of this technique to combat liver disease in the human clinic.

Li Z, Yang Z, Peng X, et al.
Nuclear factor-κB is involved in the protocadherin-10-mediated pro-apoptotic effect in multiple myeloma.
Mol Med Rep. 2014; 10(2):832-8 [PubMed] Related Publications
The gene encoding protocadherin-10 (PCDH10), a member of the cadherin superfamily, has been recently identified as a tumor suppressor gene (TSG). PCDH10 plays important roles in the apoptosis of tumor cells in some cancer types. However, the exact role of PCDH10 in multiple myeloma (MM) is largely unknown. Increasing evidence has suggested that the activation of nuclear factor-κB (NF-κB) is crucial for apoptosis in myeloma cells. In this study, we investigated the pro-apoptotic effect of PCDH10 on myeloma cells and whether this effect may involve inhibition of the NF-κB pathway. We report here, for the first time to the best of our knowledge, that PCDH10 markedly induces apoptosis of myeloma cells, accompanied by an increase in activated caspase-3 and poly-ADP‑ribose polymerase (PARP) levels, and inhibited expression of anti‑apoptotic proteins. We also demonstrate that PCDH10 inhibits the activation of NF-κB, by inhibiting the expression of the inhibitor of nuclear factor-κB (IκB) kinase subunits (IKKs) and the phosphorylation of IκBα. Moreover, the constitutive NF-κB DNA-binding activity and the expression of the NF-κB‑regulated proteins cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and intercellular adhesion molecule 1 (ICAM-1) were inhibited by PCDH10 in MM cells. These results suggest that PCDH10 induces myeloma cell apoptosis, probably by inhibiting the NF-κB pathway.

Chuang TD, Khorram O
miR-200c regulates IL8 expression by targeting IKBKB: a potential mediator of inflammation in leiomyoma pathogenesis.
PLoS One. 2014; 9(4):e95370 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
We have previously reported that leiomyoma expressed lower levels of miR-200c and elevated IL8 as compared to paired myometrium. Here we addressed the regulatory functions of miR-200c on the expression of inflammatory mediators and cellular viability using leiomyomas and paired myometrium and their isolated primary smooth muscle cells. Our results indicated that gain-of function or knockdown of miR-200c in leiomyoma smooth muscle cells (LSMC) regulated IL8 mRNA and protein expression through direct targeting of IKBKB and alteration of NF-kB activity. Additionally, leiomyoma expressed higher levels of phosphorylated IKBKB with no significant difference in the level of IKBKB mRNA and protein as compared to matched myometrium. Gain-of function of miR-200c in LSMC resulted in decreased IkBα phosphorylation and p65 nuclear translocation, which led to decreased p65 transcriptional activity of IL8 promoter, and increased caspase 3/7 activity which was not reversible following IL8 restoration. Collectively, our results suggest that NF-κB signaling pathway is a target of miR-200c regulatory function, and low level of miR-200c expression in leiomyoma by transcriptional regulation of inflammatory mediators such as IL8, in part account for development of leiomyomas.

Deng L, Li Y, Ai P, et al.
Increase in IkappaB kinase alpha expression suppresses the tumor progression and improves the prognosis for nasopharyngeal carcinoma.
Mol Carcinog. 2015; 54(2):156-65 [PubMed] Related Publications
Recent studies have suggested that the action of IkappaB kinase alpha (IKKα) as a tumor suppressor is crucial in the development of skin carcinoma, but its role in nasopharyngeal carcinoma (NPC) remains unknown. We examined the IKKα expression in specimens from 157 NPC patients by immunohistochemistry and analyzed the effect of IKKα on prognosis. The functional significance of IKKα expression in NPC cell lines was investigated by IKKα overexpression or downregulation in in vitro studies. The in vitro assays revealed that the IKKα expression was negatively correlated with the invasiveness, migration, and angiogenesis of NPC cells. Overexpression or downregulation of IKKα could significantly repress or enhance the above characteristics, respectively, and these effects were independent of IKKα kinase or EBNA1. In 157 NPC cases, IKKα was differentially expressed in NPC tissues. High expression of IKKα was associated significantly with a high disease-free survival (DFS; P = 0.002) or overall survival (OS; P = 0.014). Multivariate analyses showed that the IKKα expression was an independent risk factor for DFS (HR, 2.302; P = 0.011) and OS (HR, 3.578; P = 0.006). Our findings indicated that IKKα plays a crucial role as a tumor suppressor that suppresses the invasion, metastasis, and angiogenesis of NPC cells in vitro and correlates with the survival in NPC patients. Therefore, IKKα is not only a novel independent prognostic indicator in NPC, but also targeting IKKα expression may provide a potential therapeutic strategy for NPC.

Kim HN, Kim DH, Kim EH, et al.
Sulforaphane inhibits phorbol ester-stimulated IKK-NF-κB signaling and COX-2 expression in human mammary epithelial cells by targeting NF-κB activating kinase and ERK.
Cancer Lett. 2014; 351(1):41-9 [PubMed] Related Publications
Sulforaphane, an isothiocyanate present in cruciferous vegetables, has been reported to possess anti-inflammatory and cancer chemopreventive properties. However, the molecular mechanisms by which sulforaphane suppresses inflammation and carcinogenesis are yet to be fully elucidated. Since the aberrant expression of cyclooxygenase-2 (COX-2) links inflammation and cancer, the present study was aimed to elucidate the mechanisms by which sulforaphane modulates COX-2 overexpression in human mammary epithelial (MCF-10A) cells stimulated with a prototypic tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Treatment of MCF-10A cells with sulforaphane significantly inhibited TPA-induced expression of COX-2 protein and its mRNA transcript. Transient transfection of cells with deletion mutant constructs of COX-2 promoter revealed that the transcription factor nuclear factor-kappaB (NF-κB) plays a key role in TPA-induced COX-2 expression in MCF-10A cells. Pretreatment with sulforaphane significantly attenuated nuclear localization, DNA binding and the transcriptional activity of NF-κB through inhibition of phosphorylation and subsequent degradation of IκBα in MCF-10A cells stimulated with TPA. Sulforaphane also attenuated TPA-induced activation of IκB kinases (IKK), NF-κB-activating kinase (NAK) and extracellular signal-regulated kinase-1/2 (ERK1/2). Pharmacological inhibition of IKK or transient transfection of cells with dominant-negative mutant forms of this kinase abrogated TPA-induced NF-κB activation and COX-2 expression. In addition, the blockade of ERK1/2 activation negated the catalytic activity of IKKα, but not that of IKKβ, whereas silencing NAK by specific siRNA abrogated the IKKβ activity in TPA-treated cells. Taken together, sulforaphane inhibits TPA-induced NF-κB activation and COX-2 expression in MCF-10A cells by blocking two distinct signaling pathways mediated by ERK1/2-IKKα and NAK-IKKβ.

Garimella SV, Gehlhaus K, Dine JL, et al.
Identification of novel molecular regulators of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in breast cancer cells by RNAi screening.
Breast Cancer Res. 2014; 16(2):R41 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
INTRODUCTION: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to its receptors, TRAIL-receptor 1 (TRAIL-R1) and TRAIL-receptor 2 (TRAIL-R2), leading to apoptosis by activation of caspase-8 and the downstream executioner caspases, caspase-3 and caspase-7 (caspase-3/7). Triple-negative breast cancer (TNBC) cell lines with a mesenchymal phenotype are sensitive to TRAIL, whereas other breast cancer cell lines are resistant. The underlying mechanisms that control TRAIL sensitivity in breast cancer cells are not well understood. Here, we performed small interfering RNA (siRNA) screens to identify molecular regulators of the TRAIL pathway in breast cancer cells.
METHODS: We conducted siRNA screens of the human kinome (691 genes), phosphatome (320 genes), and about 300 additional genes in the mesenchymal TNBC cell line MB231. Forty-eight hours after transfection of siRNA, parallel screens measuring caspase-8 activity, caspase-3/7 activity, or cell viability were conducted in the absence or presence of TRAIL for each siRNA, relative to a negative control siRNA (siNeg). A subset of genes was screened in cell lines representing epithelial TNBC (MB468), HER2-amplified breast cancer (SKBR3), and estrogen receptor-positive breast cancer (T47D). Selected putative negative regulators of the TRAIL pathway were studied by using small-molecule inhibitors.
RESULTS: The primary screens in MB231 identified 150 genes, including 83 kinases, 4 phosphatases, and 63 nonkinases, as potential negative regulators of TRAIL. The identified genes are involved in many critical cell processes, including apoptosis, growth factor-receptor signaling, cell-cycle regulation, transcriptional regulation, and DNA repair. Gene-network analysis identified four genes (PDPK1, IKBKB, SRC, and BCL2L1) that formed key nodes within the interaction network of negative regulators. A secondary screen of a subset of the genes identified in additional cell lines representing different breast cancer subtypes and sensitivities to TRAIL validated and extended these findings. Further, we confirmed that small-molecule inhibition of SRC or BCL2L1, in combination with TRAIL, sensitizes breast cancer cells to TRAIL-induced apoptosis, including cell lines resistant to TRAIL-induced cytotoxicity.
CONCLUSIONS: These data identify novel molecular regulators of TRAIL-induced apoptosis in breast cancer cells and suggest strategies for the enhanced application of TRAIL as a therapy for breast cancer.

van Asbeck E, Ramalingam A, Dvorak C, et al.
Duplication at Xq28 involving IKBKG is associated with progressive macrocephaly, recurrent infections, ectodermal dysplasia, benign tumors, and neuropathy.
Clin Dysmorphol. 2014; 23(3):77-82 [PubMed] Related Publications
Duplications on Xq28 are common, although quite variable in size, but usually include the MECP2 gene. Here, we present a patient with a unique, small, 167-kb duplication at Xq28, not including MECP2. The most important gene in the duplicated region was IKBKG, mutations in which can cause a variety of distinct syndromes. Our patient's symptoms overlapped with different IKBKG-associated phenotypes, including hypohidrotic ectodermal dysplasia, incontinentia pigmenti, immunodeficiency, recurrent isolated invasive pneumococcal disease and anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, and lymphedema. In addition, she also had peripheral neuropathy, gastroparesis and various benign tumors, but no intellectual disability. Mixed syndromal presentation in several patients with IKBKG defect implies that IKBKG-related phenotypes are more like a spectrum, rather than distinct syndromes. We also suggest our patient's multisystem phenotype to be a novel contiguous gene syndrome, in which the key features include immune deficiency, macrocephaly, skin abnormalities, gastroparesis, peripheral small-fiber neuropathy, and benign tumors.

Verschuur-Maes AH, Moelans CB, de Bruin PC, van Diest PJ
Analysis of gene copy number alterations by multiplex ligation-dependent probe amplification in columnar cell lesions of the breast.
Cell Oncol (Dordr). 2014; 37(2):147-54 [PubMed] Related Publications
BACKGROUND: Columnar cell lesions (CCLs) are possible precursors of breast cancer, but little is known about the role of breast cancer-related genes in the progression of CCL to invasive breast cancer.
METHODS: Gene copy numbers of 17 breast cancer-related genes were analyzed using Multiplex Ligation-dependent Probe Amplification (MLPA) in CCL (N = 28), ductal carcinoma in situ (DCIS) grade I likely originating from CCL (N = 5), and paired CCL (N = 14/28) with DCIS (N = 7) and/or invasive carcinoma (N = 13). The genes included were BIRC5, C11orf30, CCND1, CCNE1, CDH1, CPD, EGFR, ERBB2, ESR1, FGFR1, IKBKB, MAPT, MED1, MTDH, MYC, TOP2A and TRAF4.
RESULTS: No high level gene amplifications were observed in CCL, but copy number gains were encountered for the C11orf30 (3/28), MYC, CPD, MTDH (2/28), and CCND1, CCNE1, ESR1 and TOP2A genes (1/28). In addition, CDH1 showed loss in 2/28 and TOP2A in 1/28 cases. CCLs with or without atypia exhibited comparable numbers of copy number changes (p = 0.312). Overall, the frequency of gene copy number changes increased from CCL towards DCIS and invasive carcinoma (p = 0.004). Also in the cases with synchronous lesions, the CCLs exhibited fewer copy number changes than the DCIS/invasive carcinomas.
CONCLUSIONS: CCLs carry copy number changes of several known breast cancer-related genes, thereby substantiating their role in breast carcinogenesis. Among them, CCND1 and ESR1 copy number gains and CDH1 copy number losses are of particular interest. Since the copy number changes observed were more prevalent in DCIS and invasive carcinoma than in CCL, the corresponding gene alterations may represent rather late occurring events in low nuclear grade breast carcinogenesis.

Hsiao BY, Chang TK, Wu IT, Chen MY
Rad GTPase inhibits the NFκB pathway through interacting with RelA/p65 to impede its DNA binding and target gene transactivation.
Cell Signal. 2014; 26(7):1437-44 [PubMed] Related Publications
Rad is a Ras-related small GTPase shown to inhibit cancer cell migration, and its expression is frequently lost in lung cancer cells. Here we provide evidence that Rad can negatively regulate the NFκB pathway. Overexpressing Rad in cells lowered both the basal and TNFα-stimulated transcriptional activity of NFκB. Compared with control cells, Rad-overexpressing cells displayed more cytoplasmic distribution of the NFκB subunit RelA/p65, while Rad-knockdown cells had higher levels of nuclear RelA/p65. Depleting Rad did not affect the kinetics of TNFα-induced IκB degradation, suggesting that Rad-mediated regulation of NFκB was through an IκB-independent mechanism. Expression of a nucleus-localized mutant Rad was sufficient to inhibit the NFκB transcriptional activity, whereas expressing the scaffolding protein 14-3-3γ to retain Rad in the cytoplasm alleviated the suppressive effect of Rad on NFκB. GST pull-down assays showed that Rad could directly bind to RelA/p65, and co-immunoprecipitation demonstrated that the Rad-p65 interaction primarily occurred in the nucleus. Adding Rad-containing nuclear extracts or purified GST-Rad in the electrophoretic mobility shift assays dose-dependently decreased the binding of RelA/p65 to an oligonucleotide probe containing the NFκB response element, suggesting that Rad may directly impede the interaction between RelA/p65 and DNA. Rad depletion altered the expression of an array of NFκB target genes, including upregulating MMP9. Knockdown of Rad expression in cells increased both basal and TNFα-stimulated MMP9 activities and cell invasion. Collectively, our results disclose a novel role of nuclear Rad in inhibiting the NFκB pathway function.

Kim MJ, Jung JH, Lee WS, et al.
Arsenic hexoxide enhances TNF-α-induced anticancer effects by inhibiting NF-κB activity at a safe dose in MCF-7 human breast cancer cells.
Oncol Rep. 2014; 31(5):2305-11 [PubMed] Related Publications
Arsenic hexoxide (As4O6) has been used in Korean folk remedy for the treatment of cancer since the late 1980s. Evidence suggests that the anticancer effects of As4O6 are different from those of As2O3. Tumor necrosis factor-α (TNF-α) is generally increased in advanced cancer and is closely related to cancer progression, although it has cancer-killing effects. The reason is that TNF-α activates nuclear factor-κB (NF-κB) that is involved in cell proliferation, invasion, drug resistance and metastasis. In the present study, we investigated the effects of As4O6 on NF-κB activity, NF-κB-mediated cellular responses, and NF-κB-regulated gene expressions involved in metastasis at the concentrations of As4O6 where no cytotoxicity was observed. As4O6 suppressed NF-κB activation in both TNF-α-treated and control cells, and also suppressed IκB phosphorylation in a time-dependent manner, suggesting the suppression of NF-κB results, in part, from the inhibition of IκB degradation. We also confirmed the anti-NF-κB activity of As4O6 with synergism with TNF-α by augmenting caspase-8 activation. As4O6 also suppressed NF-κB activation induced by TNF-α, and some of the downstream NF-κB-regulated proteins involved in cancer proliferation, anti-apoptosis and metastasis. In conclusion, the present study demonstrated that As4O6 has anticancer properties by inhibiting NF-κB activation and NF-κB-regulated proteins at least in part through the inhibition of IκB phosphorylation, especially in the conditions of advanced cancer where TNF-α is highly secreted.

Shi K, An J, Shan L, et al.
Survivin-2B promotes autophagy by accumulating IKK alpha in the nucleus of selenite-treated NB4 cells.
Cell Death Dis. 2014; 5:e1071 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
Survivin-2B, a known splice variant of survivin, has been reported to promote cell death in some cancer cells, although it keeps prosurvival function in others, and the mechanisms are unclear. In this report, we discovered that selenite, an antitumor agent, switched protective autophagy to apoptosis in NB4 cells. In this process, the level of survivin-2B was decreased and the interaction between IKK alpha and survivin-2B in the nucleus was attenuated, which further led to the decrease of nuclear IKK alpha. As a result, P73, a known transcript factor of UVRAG, was downregulated. Therefore, the expression of UVRAG, one of the initiators of autophagy, was inhibited. The regulatory status of survivin-2B was also proved in NB4 cells after different chemicals' exposure and in other tumor cell lines (Jurkat, HCT116). Finally, experiments in vivo confirmed that the alterations of survivin-2B, IKK alpha, P73 and UVRAG were the same as that in vitro. Taken together, survivin-2B promoted autophagy and further regulated cell death by accumulating and stabilizing IKK alpha in the nucleus.

Agarwal NK, Zhu X, Gagea M, et al.
PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase.
Oncotarget. 2014; 5(3):815-23 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
The NF-κB growth pathway is constitutively activated in many cancers but its activation mechanism is unclear in most cases. We show that PHLPP2 interacts with IKKβ kinase, decreases its phosphorylation and the subsequent NF-κB activation in cancer cells. PHLPP2 is progressively lost in glioma and colorectal cancer and acts as a bona fide tumor suppressor, depending on IKKβ expression in cells. Physiologically, IKKβ activation by growth factors requires the formation of the Bcl10-MALT1 ubiquitin-ligase complex leading to NEMO/IKKγ non-degradative ubiquitination and IKKβ phosphorylation. PHLPP2 opposes the formation of this complex through interaction with Bcl10 and competitive displacement of MALT1 from Bcl10. Conversely, PHLPP2 loss enhances Bcl10-MALT1 complex formation, NEMO ubiquitination and subsequent IKKβ phosphorylation, resulting in increased NF-κB-dependent transcription of multiple target genes. Our results reveal PHLPP2 as a new biomarker of cancer progression, and implicate it as major negative regulator of NF-κB signaling.

Yang Y, Liu L, Zhang Y, et al.
MiR-503 targets PI3K p85 and IKK-β and suppresses progression of non-small cell lung cancer.
Int J Cancer. 2014; 135(7):1531-42 [PubMed] Related Publications
A microRNA usually has the ability to coordinately repress multiple target genes and therefore are associated with many pathological conditions such as human cancer. Our understanding of the biological roles of microRNAs in lung cancer, however, remains incomplete. In this study, we identified miR-503 as a tumor-suppressive microRNA in human non-small cell lung carcinoma (NSCLC), whose expression level correlates inversely with overall survival in NSCLC patients. Ectopic expression of miR-503 suppressed tumor cell proliferation and metastasis-related traits in vitro as well as in vivo, supporting a anti-cancer role of the microRNA in NSCLC progression. Mechanistic study revealed that oncogenic PI3K p85 and IKK-β were direct targets of miR-503. Overexpression of either PI3K p85 or IKK-β partially restored the malignant properties of NSCLC cells in the presence of miR-503. Taken together, our data demonstrate miR-503 inhibits the malignant phenotype of NSCLC by targeting PI3K p85 and IKK-β and might play a suppressive role in the pathogenesis of NSCLC, thus providing new insights in developing novel diagnostic and therapeutic approaches.

Singha B, Gatla HR, Manna S, et al.
Proteasome inhibition increases recruitment of IκB kinase β (IKKβ), S536P-p65, and transcription factor EGR1 to interleukin-8 (IL-8) promoter, resulting in increased IL-8 production in ovarian cancer cells.
J Biol Chem. 2014; 289(5):2687-700 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
Proinflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8) contributes to ovarian cancer progression through its induction of tumor cell proliferation, survival, angiogenesis, and metastasis. Proteasome inhibition by bortezomib, which has been used as a frontline therapy in multiple myeloma, has shown only limited effectiveness in ovarian cancer and other solid tumors. However, the responsible mechanisms remain elusive. Here, we show that proteasome inhibition dramatically increases the IL-8 expression and release in ovarian cancer cells. The responsible mechanism involves an increased nuclear accumulation of IκB kinase β (IKKβ) and an increased recruitment of the nuclear IKKβ, p65-phosphorylated at Ser-536, and the transcription factor early growth response-1 (EGR-1) to the endogenous IL-8 promoter. Coimmunoprecipitation studies identified the nuclear EGR-1 associated with IKKβ and with p65, with preferential binding to S536P-p65. Both IKKβ activity and EGR-1 expression are required for the increased IL-8 expression induced by proteasome inhibition in ovarian cancer cells. Interestingly, in multiple myeloma cells the IL-8 release is not increased by bortezomib. Together, these data indicate that the increased IL-8 release may represent one of the underlying mechanisms responsible for the decreased effectiveness of proteasome inhibition in ovarian cancer treatment and identify IKKβ and EGR-1 as potential new targets in ovarian cancer combination therapies.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. IKBKB, Cancer Genetics Web: http://www.cancer-genetics.org/IKBKB.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 08 August, 2015     Cancer Genetics Web, Established 1999