Gene Summary

Gene:CHUK; component of inhibitor of nuclear factor kappa B kinase complex
Aliases: IKK1, IKKA, IKBKA, TCF16, NFKBIKA, IKK-alpha
Summary:This gene encodes a member of the serine/threonine protein kinase family. The encoded protein, a component of a cytokine-activated protein complex that is an inhibitor of the essential transcription factor NF-kappa-B complex, phosphorylates sites that trigger the degradation of the inhibitor via the ubiquination pathway, thereby activating the transcription factor. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:inhibitor of nuclear factor kappa-B kinase subunit alpha
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 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.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: CHUK (cancer-related)

Hung CY, Lee CH, Chiou HL, et al.
Praeruptorin-B Inhibits 12-O-Tetradecanoylphorbol-13-Acetate-Induced Cell Invasion by Targeting AKT/NF-κB via Matrix Metalloproteinase-2/-9 Expression in Human Cervical Cancer Cells.
Cell Physiol Biochem. 2019; 52(6):1255-1266 [PubMed] Related Publications
BACKGROUND/AIMS: Praeruptorins, a seselin-type coumarin, possess anti-inflammatory and antitumor promoting properties. However, molecular mechanisms through which Praeruptorin-B (Pra-B) exerts an antimetastatic effect on cervical cancer cells remain unclear.
METHODS: Cell viability was examined using the MTT assay, whereas cell migration and invasion were examined using the Boyden chamber assay. Western blotting and RT-PCR were performed to investigate the inhibitory effect of Pra-B on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase-2/-9 (MMP-2/-9) expression in HeLa cells. The findings of the luciferase assay confirmed the inhibitory effect of Pra-B on TPA-induced transcriptional activity of MMP2/-9 in HeLa cells.
RESULTS: Pra-B inhibited TPA-induced metastatic ability of human cervical cancer cells without any significant toxicity. Pra-B suppressed TPA-induced mRNA and protein expression and transcriptional activity of MMP-2/-9 in HeLa cells. Furthermore, Pra-B inhibited AKT phosphorylation but did not affect the MAPK pathway. Cotreatment of HeLa cells with TPA plus Pra-B or LY294002 (a PI3K inhibitor) reduced cell invasion and MMP-2/-9 expression and transcriptional activity. In addition, Pra-B attenuated TPA-induced nuclear translocation of NF-κB-p65/-p50, which reduced Ikk-α phosphorylation in HeLa cells. Cotreatment of HeLa cells with TPA plus Pra-B or LY294002 reduced NF-κB nuclear translocation.
CONCLUSION: These results suggested that Pra-B-mediated inhibition of TPA-induced cell metastasis involved the suppression of p-AKT/NF-κB via MMP-2/-9 expression in HeLa cells. Pra-B can be a potential antimetastatic agent against cervical cancer.

Kiliccioglu I, Konac E, Dikmen AU, et al.
Hsp-27 and NF-κB pathway is associated with AR/AR-V7 expression in prostate cancer cells.
Gene. 2019; 697:138-143 [PubMed] Related Publications
In the present study, NF-κB inhibitor BAY 11-7082 and/or Hsp-27 inhibitor KRIBB-3 agents were used to investigate the molecular mechanisms mediating androgen receptor expression on prostate cancer cell lines. The decrease observed in androgen receptor and p65 expressions, particularly at 48 h, in parallel with the decrease in the phosphorylation of the p-IKK α/β and p-Hsp-27 proteins in the LNCaP cells, indicated that androgen receptor inactivation occurred after the inhibition of the NF-κB and Hsp-27. In 22Rv1 cells, androgen receptor variant-7 was also observed to be decreased in the combined dose of 48 h. The association of this decrease with the decrease in androgen receptor and p65 expressions is a supportive result for the role of NF-κB signaling in the formation of androgen receptor variant. In androgen receptor variant-7 siRNA treatment in 22Rv1 cell lines, decrease of expression of androgen receptor variant-7 as well as decrease of expression of androgen receptor and p65 were observed. The decrease statistically significant in androgen receptor and p65 expressions was even greater when siRNA treatment was followed with low dose and time (6 h) combined treatment after transfection. We also showed that increased Noxa and decreased Bcl-2 protein level, indicated that apoptotic induction after this combination. In conclusion, inhibition of NF-κB and Hsp-27 is also important, along with therapies for androgen receptor variant-7 inhibition.

Wei D, Shen B, Wang W, et al.
MicroRNA‑199a‑5p functions as a tumor suppressor in oral squamous cell carcinoma via targeting the IKKβ/NF‑κB signaling pathway.
Int J Mol Med. 2019; 43(4):1585-1596 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) have been shown to have a significant role in the progression of several types of cancer, including oral squamous cell carcinoma (OSCC). However, the biological function and regulatory mechanisms of miRNAs in OSCC remain to be fully elucidated. The aim of the present study was to investigate the role of miRNAs in OSCC and the relevant mechanism. Using a microarray, it was found that miRNA (miR)‑199a‑5p was one of the most downregulated miRNAs in OSCC tissues. A low expression of miR‑199a‑5p was closely associated with tumor differentiation, lymph node metastasis, tumor‑node‑metastasis stage, and overall survival rate. Functionally, the overexpression of miR‑199a‑5p suppressed cell proliferation, induced G0/G1 cell cycle arrest, and promoted the apoptosis of Tca8113 and SCC‑4 cells. Subsequently, inhibitor of nuclear factor‑κB (NF‑κB) kinase β (IKKβ), an important regulator of NF‑κB activation, was identified as a direct target of miR‑199‑5p. An inverse correlation was found between miR‑199a‑5p and IKKβ in tumor tissues. Further investigations revealed that the overexpression of IKKβ efficiently abrogated the influences caused by the overexpression of miR‑199a‑5p. It was also found that the miR‑199a‑5p‑mediated anticancer effects were dependent on the inhibition of NF‑κB activation. These findings indicate that miR‑199a‑5p functions as a tumor suppressor through regulation of the NF‑κB pathway by targeting IKKβ in OSCC.

Shao YY, Chang ZP, Cheng Y, et al.
Shaoyao-Gancao Decoction alleviated hyperandrogenism in a letrozole-induced rat model of polycystic ovary syndrome by inhibition of NF-κB activation.
Biosci Rep. 2019; 39(1) [PubMed] Free Access to Full Article Related Publications
Shaoyao-Gancao Decoction (SGD) has been widely used for the treatment of gynopathy. The present study aimed to evaluate the therapeutic effect and potential mechanism of SGD on hyperandrogenism in polycystic ovary syndrome (PCOS) rats. In the present work, SGD was orally administrated to the PCOS rats at the dose of 12.5, 25, and 50 g/kg/d for 14 consecutive days. UPLC-MS/MS was performed to identify the main chemical components of SGD. Body weight, ovarian weight, cystic dilating follicles, and serum levels of steroid hormones were tested to evaluate the therapeutic effect of SGD. In order to further clarify the underlying mechanism, we also measured mRNA and the protein levels of NF-κB, NF-κB p65, P-NF-κB p65, and IκB by RT-qPCR and Western blotting techniques. Our results showed that SGD treatment significantly alleviated hyperandrogenism in PCOS rats as evidenced by reduced serum levels of T and increased E

Shen X, Zhang J, Zhang X, et al.
Retinoic Acid-Induced Protein 14 (RAI14) Promotes mTOR-Mediated Inflammation Under Inflammatory Stress and Chemical Hypoxia in a U87 Glioblastoma Cell Line.
Cell Mol Neurobiol. 2019; 39(2):241-254 [PubMed] Related Publications
Retinoic acid-induced 14 is a developmentally regulated gene induced by retinoic acid and is closely associated with NIK/NF-κB signaling. In the present study, we examined the effect of RAI14 on mTOR-mediated glial inflammation in response to inflammatory factors and chemical ischemia. A U87 cell model of LPS- and TNF-α-induced inflammation was used to investigate the role of RAI14 in glial inflammation. U87 cells were treated with siR-RAI14 or everolimus to detect the correlation between mTOR, RAI14, and NF-κB. CoCl

Fan Y, Ou L, Fan J, et al.
HepaCAM Regulates Warburg Effect of Renal Cell Carcinoma via HIF-1α/NF-κB Signaling Pathway.
Urology. 2019; 127:61-67 [PubMed] Related Publications
OBJECTIVE: To investigate how hepatocyte cell adhesion molecule (hepaCAM) regulates cancer energy metabolism through hypoxia-inducible factor (HIF-1α) in renal cell carcinoma (RCC).
MATERIALS AND METHODS: The expression of hepaCAM and HIF-1α in RCC tissue samples was examined by immunohistochemistry. Glucose consumption and lactate production assays were used to detect metabolic activity in RCC cell lines. P65 and IκB kinase (IKKβ) mRNA and protein expression were detected using quantitative real-time polymerase chain reaction and western blotting, respectively. Nuclear translocation of P65 was observed by immunofluorescence staining after re-expressing hepaCAM. The luciferase reporter assay was applied to validate the transcriptional activity of HIF-1α.
RESULTS: HIF-1α expression was elevated and hepaCAM suppressed in RCC compared with adjacent normal tissues. Furthermore, hepaCAM re-expression significantly decreased glycolytic metabolism in RCC cell lines, and reduced HIF-1α, IKKβ, and P65 expression. The expression of HIF-1α, GLUT1, LDHA, and PKM2 were further reduced with combined hepaCAM overexpression and treatment with the NF-κB inhibitor BAY11-7082, compared to hepaCAM overexpression alone. Additionally, hepaCAM decreased the transcriptional activity of HIF-1α and blocked P65 nuclear translocation by the NF-κB pathway.
CONCLUSION: Our data suggest that hepaCAM suppresses the Warburg effect via the HIF-1α/NF-κB pathway in RCC, which is a facilitating factor in hepaCAM-reduced tumorigenesis.

Gayed DT, Wodeyar J, Wang ZX, et al.
Prognostic values of inhibitory κB kinases mRNA expression in human gastric cancer.
Biosci Rep. 2019; 39(1) [PubMed] Free Access to Full Article Related Publications

Ta N, Huang X, Zheng K, et al.
miRNA-1290 Promotes Aggressiveness in Pancreatic Ductal Adenocarcinoma by Targeting IKK1.
Cell Physiol Biochem. 2018; 51(2):711-728 [PubMed] Related Publications
BACKGROUND/AIMS: MicroRNAs (miRNAs) are a group of non-coding RNAs that play diverse roles in pancreatic carcinogenesis. In pancreatic ductal adenocarcinoma (PDAC), NF-kB is constitutively activated in most patients and is linked to a mutation in KRAS via IkB kinase complex 1 (IKK1, also known as IKKa). We investigated the link between PDAC aggressiveness and miR-1290.
METHODS: We used miRCURYTM LNA Array and in situ hybridization to investigate candidate miRNAs and validated the findings with PCR. The malignant behavior of cell lines was assessed with Cell Counting Kit-8, colony formation, and Transwell assays. A dual-luciferase reporter assay was used to evaluate the interaction between miR-1290 and IKK1. Protein expression was observed by western blotting.
RESULTS: In this study, 36 miRNAs were dysregulated in high-grade pancreatic intraepithelial neoplasia (PanIN) and PDAC tissues compared with low-grade PanIN tissues. The area under the curve values of miR-1290 and miR-31-5p were 0.829 and 0.848, respectively (95% confidence interval, 0.722-0.936 and 0.749-0.948, both P < 0.001). There was a significant correlation between miR-1290 and histological differentiation (P = 0.029), pT stage (P = 0.006), and lymph node metastasis (P = 0.001). In addition, the in vitro work showed that miR-1290 promoted PDAC cell proliferation, invasion, and migration. Western blotting and the dual-luciferase reporter assay showed that miR-1290 promoted cancer aggressiveness by directly targeting IKK1. The synergist effect of miR-1290 on the proliferation and metastasis of PDAC cells was attenuated and enhanced by IKK1 overexpression and knockdown, respectively. Consistent with the in vitro results, a subcutaneous tumor mouse model showed that miR-1290 functioned as a potent promoter of PDAC in vivo.
CONCLUSION: MiR-1290 may act as an oncogene by directly targeting the 3'-untranslated region of IKK1, and the miR-1290/IKK1 pathway may prove to be a novel diagnostic and therapeutic target for PDAC.

Moeng S, Seo HA, Hwang CY, et al.
MicroRNA-107 Targets IKBKG and Sensitizes A549 Cells to Parthenolide.
Anticancer Res. 2018; 38(11):6309-6316 [PubMed] Related Publications
BACKGROUND/AIM: Patients with advanced non-small cell lung cancer (NSCLC) frequently face a dismal prognosis because of lack of curative therapies. We, therefore, conducted a preclinical investigation of the therapeutic efficacy of microRNA-107 (miR-107).
MATERIALS AND METHODS: The effects of miR-107 on cell proliferation and target gene expression were studied. Combinatorial effects of miR-107 and parthenolide were evaluated.
RESULTS: Cell proliferation was repressed in A549 NSCLC cells transfected with miR-107. Inhibitor of nuclear factor kappa B kinase subunit gamma was directly targeted by miR-107. Overexpression of miR-107 in A549 cells sensitized them to parthenolide along with a marked reduction of cyclin-dependent kinase 2.
CONCLUSION: Our findings unveil an important biological function of miR-107 in regulating lung cancer cell proliferation and elevating an antiproliferative effect of parthenolide on lung cancer cells, suggesting that miR-107 could be beneficial benefit treatment for advanced NSCLC.

Gao Y, Liu H, Wang H, et al.
Baicalin inhibits breast cancer development via inhibiting IĸB kinase activation in vitro and in vivo.
Int J Oncol. 2018; 53(6):2727-2736 [PubMed] Related Publications
The aim of the present study was to investigate the effect and therapeutic potential of baicalin in breast cancer. Baicalin is used to treat inflammatory diseases. The effects of baicalin were assessed in breast cancer MCF-7 and MDA-MB‑231 cells, and human breast cancer xenograft mice. Cells were treated with 0, 20 or 30 µM baicalin for 48 h, while xenograft mice were treated with intraperitoneal injection of 0, 100 or 200 mg/kg baicalin for 30 days. The results demonstrated that treatment with baicalin dose-dependently suppressed breast cancer cell invasion, migration and proliferation, and also induced G1/S-phase cell cycle arrest in vitro and in vivo. Baicalin alleviated inflammation injury and inhibited the secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-1β, thus suppressing nuclear factor (NF)-ĸB-p65 activation via inhibition of IĸB kinase. Investigation of the mechanism underlying baicalin activity indicated that it inhibited protein expression of NF-ĸB-p65, leading to NF-ĸB‑induced increased expression of CCND1, BCL2, BIRC2 and BIRC3, thus inhibiting cell proliferation, invasion and migration and suppressing anti-apoptotic factors in vitro and in vivo. In addition, baicalin did not affect non-tumorigenic normal breast epithelial cells. These results indicate that baicalin may exert therapeutic effects in breast cancer.

Nafees S, Mehdi SH, Zafaryab M, et al.
Synergistic Interaction of Rutin and Silibinin on Human Colon Cancer Cell Line.
Arch Med Res. 2018; 49(4):226-234 [PubMed] Related Publications
AIM OF THE STUDY: Rutin and Silibinin are active flavonoid compounds, well-known for possessing multiple biological activities. We have studied how Rutin and Silibinin in combination modulate wide range intracellular signaling cascades as evidenced by in-vitro research. Data obtained from preclinical studies provide evidence to be supportive to bridge basic and translational studies.
METHODS: In this study, cytotoxic effect of Rutin and Silibinin individually and in combination on the viability of colon cancer cell line (HT-29) was revealed using the MTT assay. Mechanism involved in the cytotoxic effect were then investigated in terms of apoptosis using comet assay, DNA fragmentation and fluorescent microscopy analyses. The apoptosis associated proteins viz; Caspase-3, 8, 9, Bax, Bcl-2, p53, inflammation associated proteins viz; NFκB, IKK-α IKK-β and MAPK pathway associated proteins viz; p38 and MK-2 were determined by western-blot and Real Time-PCR analysis.
RESULTS: Results suggest that Rutin and Silibinin produce anticancer effects via induction of apoptosis as well as regulating the expressions of genes related to apoptosis, inflammation and MAPK pathway proteins more effectively in combination than individually.
CONCLUSION: Our study supports the viability of developing Rutin and Silibinin in combination as a novel therapeutic prodrug for colon cancer treatment and may have a promising role in the development of new anticancer drugs in the future.

Arafat K, Al Kubaisy E, Sulaiman S, et al.
SMARCAD1 in Breast Cancer Progression.
Cell Physiol Biochem. 2018; 50(2):489-500 [PubMed] Related Publications
BACKGROUND/AIMS: Breast cancer is the most common cancer in women worldwide, and within this cancer type, triple-negative breast cancers have the worst prognosis. The identification of new genes associated with triple-negative breast cancer progression is crucial for developing more specific anti-cancer targeted therapies, which could lead to a better management of these patients. In this context, we have recently demonstrated that SMARCAD1, a DEAD/H box-containing helicase, is involved in breast cancer cell migration, invasion, and metastasis. The aim of this study was to investigate the impact of the stable knockdown of SMARCAD1 on human breast cancer cell progression.
METHODS: Using two different designs of shRNA targeting SMARCAD1, we investigated the impact of the stable knockdown of SMARCAD1 on human breast cancer cell proliferation and colony growth in vitro and on tumour growth in chick embryo and nude mouse xenograft models in vivo using MDA-MB-231 (ER-/PR-/ HER2-) and T47D (ER+/PR+/-/HER2-) human breast cancer cell lines.
RESULTS: We found that SMARCAD1 knockdown resulted in a significant decrease in breast cancer cell proliferation and colony formation, leading to the significant inhibition of tumour growth in both the chick embryo and nude mouse xenograft models. This inhibition was due, at least in part, to a decrease in IKKβ expression.
CONCLUSION: These results indicate that SMARCAD1 is involved in breast cancer progression and can be a promising target for breast cancer therapy.

Gong Y, Luo X, Yang J, et al.
RIPK4 promoted the tumorigenicity of nasopharyngeal carcinoma cells.
Biomed Pharmacother. 2018; 108:1-6 [PubMed] Related Publications
RIPK4 (receptor interacting serine/threonine kinase 4) has been reported to be aberrantly expressed in several cancer types. However, its expression pattern and functions in nasopharyngeal carcinoma (NPC) have never been reported. In this study, we have shown that the expression of RIPK4 was up-regulated in NPC tissues. RIPK4 promoted the growth and anchorage-independent growth of NPC cells, and down-regulation of RIPK4 inhibited the growth of NPC cells both in the plate-based culture and on the soft agar. Moreover, RIPK4 promoted the expression of VEGF in the NPC cells and induced the tube formation of HUVEC, and Axitinib (the inhibitor for VEGF receptor) inhibited the tumorigenesis driven by RIPK4. In the molecular mechanism study, RIPK4 was found to enhance the interaction between IKKα and IKKβ, and activated NF-kB signaling. Taken together, our study demonstrated the oncogenic roles of RIPK4 in NPC and suggested that RIPK4 might be a therapeutic target.

Choi J, Ahn SS, Lim Y, et al.
Inhibitory Effect of
Int J Mol Sci. 2018; 19(9) [PubMed] Free Access to Full Article Related Publications
CXC motif chemokine ligand 10 (CXCL10) and its receptor CXC motif chemokine receptor 3 (CXCR3), play important roles in the motility of breast cancer cells.

Niu B, Coslo DM, Bataille AR, et al.
In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets.
Nucleic Acids Res. 2018; 46(16):8385-8403 [PubMed] Free Access to Full Article Related Publications
The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor orchestrating complex roles in cell and systems biology. Species differences in CAR's effector pathways remain poorly understood, including its role in regulating liver tumor promotion. We developed transgenic mouse models to assess genome-wide binding of mouse and human CAR, following receptor activation in liver with direct ligands and with phenobarbital, an indirect CAR activator. Genomic interaction profiles were integrated with transcriptional and biological pathway analyses. Newly identified CAR target genes included Gdf15 and Foxo3, important regulators of the carcinogenic process. Approximately 1000 genes exhibited differential binding interactions between mouse and human CAR, including the proto-oncogenes, Myc and Ikbke, which demonstrated preferential binding by mouse CAR as well as mouse CAR-selective transcriptional enhancement. The ChIP-exo analyses also identified distinct binding motifs for the respective mouse and human receptors. Together, the results provide new insights into the important roles that CAR contributes as a key modulator of numerous signaling pathways in mammalian organisms, presenting a genomic context that specifies species variation in biological processes under CAR's control, including liver cell proliferation and tumor promotion.

Uddin MM, Zou Y, Sharma T, et al.
Proteasome inhibition induces IKK-dependent interleukin-8 expression in triple negative breast cancer cells: Opportunity for combination therapy.
PLoS One. 2018; 13(8):e0201858 [PubMed] Free Access to Full Article Related Publications
Triple negative breast cancer (TNBC) cells express increased levels of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8), which promotes their proliferation and migration. Because TNBC patients are unresponsive to current targeted therapies, new therapeutic strategies are urgently needed. While proteasome inhibition by bortezomib (BZ) or carfilzomib (CZ) has been effective in treating hematological malignancies, it has been less effective in solid tumors, including TNBC, but the mechanisms are incompletely understood. Here we report that proteasome inhibition significantly increases expression of IL-8, and its receptors CXCR1 and CXCR2, in TNBC cells. Suppression or neutralization of the BZ-induced IL-8 potentiates the BZ cytotoxic and anti-proliferative effect in TNBC cells. The IL-8 expression induced by proteasome inhibition in TNBC cells is mediated by IκB kinase (IKK), increased nuclear accumulation of p65 NFκB, and by IKK-dependent p65 recruitment to IL-8 promoter. Importantly, inhibition of IKK activity significantly decreases proliferation, migration, and invasion of BZ-treated TNBC cells. These data provide the first evidence demonstrating that proteasome inhibition increases the IL-8 signaling in TNBC cells, and suggesting that IKK inhibitors may increase effectiveness of proteasome inhibitors in treating TNBC.

Zhang Y, Xu Z, Ding J, et al.
HZ08 suppresses RelB-activated MnSOD expression and enhances Radiosensitivity of prostate Cancer cells.
J Exp Clin Cancer Res. 2018; 37(1):174 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The development of radioresistance is one of main causes for therapeutic failure of prostate cancer (PCa). The present study aims to investigate the function and the related mechanism by which HZ08 sensitizes radiotherapeutic efficiency to treat aggressive PCa cells.
METHODS: PCa cells were pretreated with HZ08 (6,7-dimethoxy-1-(3,4-dimethoxy) benzyl-2-(N-n-octyl-N'-cyano) guanyl-1,2,3,4-tetrahydroisoquinoline) and followed by ionizing radiation (IR) treatment. Cytotoxicity in the treated cells was analyzed to assess the radiosensitization capacity of HZ08 by flow cytometry, MTT and colony survival assays. The cellular levels of reactive oxygen species (ROS) and oxygen consumption rates (OCR) were measured using specific ROS detection probes and a Seahorse XF96 Analyzer, respectively. RelB binding to the NF-κB intronic enhancer region of the human SOD2 gene was determined using a ChIP assay. The levels of phosphorylation of PI3K, Akt and IKKα were quantified and further confirmed using a PI3K inhibitor. Finally, the synergistic effect of HZ08 on radiosensitization of PCa cells was validated using a mouse xenograft tumor model.
RESULTS: HZ08 enhanced radiosensitivity of PCa cells through increasing ROS and declining mitochondrial respiration due to suppression of mitochondrial antioxidant enzyme MnSOD. Mechanistically, HZ08 appeared to inhibit PI3K/Akt/IKKα signaling axis, resulting in transcriptional repression of MnSOD expression by preventing RelB nuclear translocation.
CONCLUSIONS: HZ08 can serve as a useful radiosensitizing agent to improve radiotherapy for treating aggressive PCa cells with high level of constitutive RelB. The present study suggests a promising approach for enhancing radiotherapeutic efficiency to treat advanced PCa by inhibiting antioxidant defense function.

Lu W, Mao Y, Chen X, et al.
Fordin: A novel type I ribosome inactivating protein from Vernicia fordii modulates multiple signaling cascades leading to anti-invasive and pro-apoptotic effects in cancer cells in vitro.
Int J Oncol. 2018; 53(3):1027-1042 [PubMed] Free Access to Full Article Related Publications
Fordin, which is derived from Vernicia fordii, is a novel type I ribosome inactivating protein (RIP) with RNA N-glycosidase activity. In the present study, fordin was expressed by Escherichia coli and purified using nickel affinity chromatography. Previous studies have demonstrated RIP toxicity in a variety of cancer cell lines. To understand the therapeutic potential of fordin on tumors, the present study investigated the effects of fordin on the viability of several tumor and normal cell lines. The results demonstrated that fordin induced significant cytotoxicity in four cancer cell lines, compared with the normal cell line. Specifically, profound apoptosis and inhibition of cell invasion were observed following fordin exposure in U-2 OS and HepG2 cells; however, the molecular mechanism underlying the action of RIP remains to be fully elucidated. In the present study, it was found that the anticancer effects of fordin were associated with suppression of the nuclear factor (NF)-κB signaling pathway. In U-2 OS and HepG2 cells, fordin inhibited the expression of inhibitor of NF-κB (IκB) kinase, leading to downregulation of the phosphorylation level of IκB, which quelled the nuclear translocation of NF-κB. Fordin also reduced the mRNA and protein levels of NF-κB downstream targets associated with cell apoptosis and metastasis, particularly B-cell lymphoma‑2-related protein A1 (Blf-1) and matrix metalloproteinase (MMP)-9. The inactivation of NF-κB and the reduction in the expression levels of Blf-1 and MMP-9 mediated by fordin were also confirmed by co-treatment with lipopolysaccharide or p65 small interfering RNA. These findings suggested a possible mechanism for the fordin-induced effect on tumor cell death and metastasis. The results of the present study demonstrated the multiple anticancer effects of fordin in U-2 OS and HepG2 cells, in part by inhibiting activation of the NF-κB signaling pathway.

Huang Y, Chen G, Wang Y, et al.
Inhibition of microRNA-16 facilitates the paclitaxel resistance by targeting IKBKB via NF-κB signaling pathway in hepatocellular carcinoma.
Biochem Biophys Res Commun. 2018; 503(2):1035-1041 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a common malignant tumor usually resistant to chemotherapy. MicroRNAs play important roles in modulation of carcinogenesis and chemoresistance, which miR-16 has been reported to mediate chemoresistance in many types of cancers. However, the role of miR-16 in HCC remains unknown. The aim of this study was to investigate whether miR-16 is participated in chemoresistance in HCC and shed light on the underlying molecular mechanisms. The findings of the current study discover that miR-16 is down-regulated in HCC tissue and cell lines. The results demonstrate that the inhibition of miR-16 renders resistance to paclitaxel in vitro and in vivo by targeting IKBKB via NF-κB signaling pathway, suggesting that miR-16 may be a meaningful therapeutic potential to overcome drug resistance in HCC.

Ishikawa C, Senba M, Mori N
Mitotic kinase PBK/TOPK as a therapeutic target for adult T‑cell leukemia/lymphoma.
Int J Oncol. 2018; 53(2):801-814 [PubMed] Related Publications
Adult T‑cell leukemia/lymphoma (ATLL) is a disorder involving human T-cell leukemia virus type 1 (HTLV‑1)-infected T‑cells characterized by increased clonal neoplastic proliferation. PDZ-binding kinase (PBK) [also known as T‑lymphokine-activated killer cell-originated protein kinase (TOPK)] is a serine/threonine kinase expressed in proliferative cells and is phosphorylated during mitosis. In this study, the expression and phosphorylation of PBK/TOPK were examined by western blot analysis and RT‑PCR. We found that PBK/TOPK was upregulated and phosphorylated in HTLV‑1-transformed T‑cell lines and ATLL‑derived T‑cell lines. Notably, CDK1/cyclin B1, which phosphorylates PBK/TOPK, was overexpressed in these cells. HTLV‑1 infection upregulated PBK/TOPK expression in peripheral blood mononuclear cells (PBMCs) in co-culture assays. The potent PBK/TOPK inhibitors, HI‑TOPK‑032, and fucoidan from brown algae, decreased the proliferation and viability of these cell lines in a dose‑dependent manner. By contrast, the effect of HI‑TOPK‑032 on PBMCs was less pronounced. Treatment with HI‑TOPK‑032 resulted in G1 cell cycle arrest, and decreased CDK6 expression and pRb phosphorylation, which are critical determinants of progression through the G1 phase. In addition, HI‑TOPK‑032 induced apoptosis, as evidenced by morphological changes, the cleavage of poly(ADP-ribose) polymerase with the activation of caspase‑3, -8 and -9, and an increase in the sub‑G1 cell population and APO2.7-positive cells. Moreover, HI‑TOPK‑032 inhibited the expression of cellular inhibitor of apoptosis 2 (c-IAP2), X-linked inhibitor of apoptosis protein (XIAP), survivin and myeloid cell leukemia‑1 (Mcl‑1), and induced the expression of Bak and interferon-induced protein with tetratricopeptide repeats (IFIT)1, 2 and 3. It is noteworthy that the use of this inhibitor led to the inhibition of the phosphorylation of IκB kinase (IKK)α, IKKβ, IκBα, phosphatase and tensin homolog (PTEN) and Akt, and to the decreased protein expression of JunB and JunD, suggesting that PBK/TOPK affects the nuclear factor-κB, Akt and activator protein‑1 signaling pathways. In vivo, the administration of HI‑TOPK‑032 suppressed tumor growth in an ATLL xenograft model. Thus, on the whole, this study on the identification and functional analysis of PBK/TOPK suggests that this kinase is a promising molecular target for ATLL treatment.

Shahbazi R, Cheraghpour M, Homayounfar R, et al.
Hesperidin inhibits insulin-induced phosphoinositide 3-kinase/Akt activation in human pre-B cell line NALM-6.
J Cancer Res Ther. 2018 Apr-Jun; 14(3):503-508 [PubMed] Related Publications
Context: It has been shown that hesperidin induces apoptosis in NALM-6 cells through inhibition of nuclear factor-kappa B (NF-κB) activation.
Aims: To investigate the effect of hesperidin on inhibition of NF-κB activation through blocking phosphoinositide 3-kinase (PI3K)/Akt pathway as a main target in cancer treatment, in NALM-6 cells.
Materials and Methods: NALM-6 cells were incubated with two concentrations of hesperidin (25, 50 μM) in the presence or absence of insulin (100 nM), as a potent activator of Akt. The cytotoxic activity of hesperidin was determined by 3-(4,5-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell apoptotic death was measured by ELISA test using cell death detection ELISA
Results: Hesperidin (both concentrations) significantly reduced cells survival in the presence and absence of insulin compared to untreated cells in a time-dependent manner (P < 0.05). Hesperidin also significantly increased apoptosis in NALM-6 cells even in hyperinsulinemia condition (P < 0.0001). Hesperidin inhibited insulin-induced phosphorylation and activation of Akt, IκBα, and GSK-3β and decreased expression of IKKα.
Conclusion: The results of this study demonstrated that cytotoxic and proapoptotic actions of hesperidin are partly mediated through the suppression of PI3K3/Akt/IKK signaling pathway. So, hesperidin might act as a chemotherapeutic agent by targeting cell survival pathways.

House CD, Grajales V, Ozaki M, et al.
IΚΚε cooperates with either MEK or non-canonical NF-kB driving growth of triple-negative breast cancer cells in different contexts.
BMC Cancer. 2018; 18(1):595 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metastatic breast cancer carries a poor prognosis despite the success of newly targeted therapies. Treatment options remain especially limited for the subtype of triple negative breast cancer (TNBC). Several signaling pathways, including NF-κB, are altered in TNBC, and the complexity of this disease implies multi-faceted pathway interactions. Given that IKKε behaves as an oncogene in breast cancer, we hypothesized that IKKε regulates NF-κB signaling to control diverse oncogenic functions in TNBC.
METHODS: Vector expression and RNA interference were used to investigate the functional role of IKKε in triple-negative breast cancer cells. Viability, protein expression, NF-κB binding activity, invasion, anoikis, and spheroid formation were examined in cells expressing high or low levels of IKKε, in conjunction with p52 RNA interference or MEK inhibition.
RESULTS: This study found that non-canonical NF-κB p52 levels are inversely proportional to ΙΚΚε, and growth of TNBC cells in anchorage supportive, high-attachment conditions requires IKKε and activated MEK. Growth of these cells in anchorage resistant conditions requires IKKε and activated MEK or p52. In this model, IKKε and MEK cooperate to support overall viability whereas the p52 transcription factor is only required for viability in low attachment conditions, underscoring the contrasting roles of these proteins.
CONCLUSIONS: This study illustrates the diverse functions of IKKε in TNBC and highlights the adaptability of NF-κB signaling in maintaining cancer cell survival under different growth conditions. A better understanding of the diversity of NF-κB signaling may ultimately improve the development of novel therapeutic regimens for TNBC.

Inoue Y, Shimizu A, Suto M, et al.
Cutaneous squamous cell carcinoma, thyroid cancer and Langerhans cell histiocytosis in a patient with X-linked recessive Mendelian susceptibility to mycobacterial diseases with a nuclear factor-κB essential modifier mutation.
J Dermatol. 2018; 45(8):1017-1019 [PubMed] Related Publications
Nuclear factor (NF)-κB essential modifier (NEMO), also known as IκB kinase subunit-γ (IKKγ), is a pivotal molecule in the NF-κB signaling pathway. Mutations of NEMO cause incontinentia pigmenti and X-linked ectodermal dysplasia with immunodeficiency. Mendelian susceptibility to mycobacterial diseases (MSMD), which confers an almost selective predisposition to mycobacterial infection, is also caused by NEMO mutations. We herein report the first case of a patient with X-linked recessive (XR) MSMD who developed cutaneous squamous cell carcinoma, thyroid cancer and Langerhans cell histiocytosis. The relationship between NEMO mutation and oncogenesis is discussed.

Singh MK, Pushker N, Meel R, et al.
Does NEMO/IKKγ protein have a role in determining prognostic significance in uveal melanoma?
Clin Transl Oncol. 2018; 20(12):1592-1603 [PubMed] Related Publications
PURPOSE: Uveal melanoma, although a rare form of cancer, is the most common primary malignancy of the eye in adults. Nuclear factor-κB (NF-κB) is a transcription factor that transactivates genes involved in the regulation of cell growth, apoptosis, angiogenesis, and metastasis, but the molecular mechanisms that negatively regulate NF-κB activation are not fully understood. NF-κB can also be activated by DNA damage pathway through NEMO protein. Therefore, the objective of this study is to elucidate the role of NEMO/IKKγ protein in uveal melanoma patients.
METHODS: Seventy-five formalin-fixed paraffin-embedded prospective tissues of uveal melanoma were included in the present study. These cases were reviewed and investigated for the expression of NEMO/IKKγ protein by immunohistochemistry and validated by western blotting along with the qRT-PCR for mRNA expression. Expression levels were correlated with the clinicopathological parameters and patients' outcome.
RESULTS: Immunohistochemistry showed cytoplasmic expression of NEMO/IKKγ expression in only 22 out of 75 (29.33%) cases. This result was confirmed by western blotting, and correlated well with the immunohistochemical expression of NEMO/IKKγ protein (48 kDa). In addition, downregulation of this gene was found in 87.93% of the cases when compared with the normal tissues. On statistical analysis, loss of NEMO/IKKγ protein was correlated with neovascularization, high mitotic count, and presence of vascular loop (p < 0.05). There was less overall survival rate with low expression of NEMO/IKKγ protein in patients with uveal melanoma.
CONCLUSION: This was the first study suggesting the relevant role of NEMO/IKKγ protein, and highlights the prognostic significance with outcome in uveal melanoma patients. This protein might be used as a screening biomarker in these patients after large-scale validation and translational studies.

Ji DG, Guan LY, Luo X, et al.
Inhibition of MALAT1 sensitizes liver cancer cells to 5-flurouracil by regulating apoptosis through IKKα/NF-κB pathway.
Biochem Biophys Res Commun. 2018; 501(1):33-40 [PubMed] Related Publications
Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is involved in tumor cell growth process. However, its role and molecular mechanism in liver cancer is still not fully understood. In this study, we found that MALAT1 was significantly expressed in liver cancer cell lines. And knockdown of MALAT1 suppressed proliferation, migration and invasion of HepG2 cells, accompanied with decrease of Rho-associated coiled-coil-forming protein kinase 1 (ROCK1), α-smooth muscle actin (α-SMA), N-cadherin, Vimentin and TWIST. Significantly, MALAT1 deletion sensitized HepG2 cells to 5-FU-induced cell cycle arrest in G1 phase, as evidenced by the significant reduction in Cyclin D1 and CDK4 and increase in p53, p21 and p27 protein levels. In addition, MALAT1 knockdown triggered 5-FU induced apoptosis in HepG2 cells by inducing intrinsic apoptosis-related signals, including Cyto-c, Apaf-1, cleaved Caspase-9/-7/-3 and poly (ADP-ribose) polymerase (PARP). Furthermore, phosphorylated nuclear factor-κB (p-NF-κB) was also down-regulated by MALAT1 silence. Importantly, suppression of IKKα/NF-κB significantly elevated apoptosis and reduced liver cancer cell viability in MALAT1-knockdown cells with 5-FU incubation. The nude mice transplantation model also confirmed the promoted sensitivity of MALAT1-silenced HepG2 cells to 5-FU by blocking tumor cell proliferation and inducing apoptosis. Therefore, our data supplied a potential mechanism by which knockdown of MALAT1 might play an important role in augmenting sensitivity of HepG2 cells to 5-FU in therapeutic approaches, demonstrating suppressing of MALAT1 may serve as a combination with chemotherapeutic agents in liver cancer treatment.

Du J, He Y, Li P, et al.
IL-8 regulates the doxorubicin resistance of colorectal cancer cells via modulation of multidrug resistance 1 (MDR1).
Cancer Chemother Pharmacol. 2018; 81(6):1111-1119 [PubMed] Related Publications
Cytokines play important roles in tumorigenesis and progression of cancer cells, while their functions in drug resistance remain to be illustrated. We successfully generated doxorubicin (Dox)-resistant CRC HCT-116 and SW480 cells (namely HCT-116/Dox and SW480/Dox, respectively). Cytokine expression analysis revealed that IL-8, while not FGF-2, EGF, TGF-β, IL-6, or IL-10, was significantly increased in Dox-resistant CRC cells as compared with their corresponding parental cells. Targeted inhibition of IL-8 via siRNAs or its inhibitor reparixin can increase the Dox sensitivity of HCT-116/Dox and SW480/Dox cells. The si-IL-8 can decrease the mRNA and protein expression of multidrug resistance 1 (MDR1, encoded by ABCB1), while has no effect on the expression of multidrug resistance-associated protein 1 (ABCC1), in CRC Dox-resistant cells. IL-8 can increase the phosphorylation of p65 and then upregulate the binding between p65 and promoter of ABCB1. BAY 11-7082, the inhibitor of NF-κB, suppressed the recombination IL-8 (rIL-8) induced upregulation of ABCB1. It confirmed that NF-κB is involved in IL-8-induced upregulation of ABCB1. rIL-8 also increased the phosphorylation of IKK-β, which can further activate NF-κB, while specific inhibitor of IKK-β (ACHP) can reverse rIL-8-induced phosphorylation of p65 and upregulation of MDR1. These results suggested that IL-8 regulates the Dox resistance of CRC cells via modulation of MDR1 through IKK-β/p65 signals. The targeted inhibition of IL-8 might be an important potential approach to overcome the clinical Dox resistance in CRC patients.

Hleihel R, Khoshnood B, Dacklin I, et al.
The HTLV-1 oncoprotein Tax is modified by the ubiquitin related modifier 1 (Urm1).
Retrovirology. 2018; 15(1):33 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy secondary to chronic human T-cell lymphotropic virus 1 infection, triggered by the virally encoded oncoprotein Tax. The transforming activity and subcellular localization of Tax is strongly influenced by posttranslational modifications, among which ubiquitylation and SUMOylation have been identified as key regulators of the nuclear/cytoplasmic shuttling of Tax, as well as its ability to activate NF-κB signaling.
RESULTS: Adding to the complex posttranslational modification landscape of Tax, we here demonstrate that Tax also interacts with the ubiquitin-related modifier 1 (Urm1). Conjugation of Urm1 to Tax results in a redistribution of Tax to the cytoplasm and major increase in the transcription of the NF-ĸB targets Rantes and interleukin-6. Utilizing a tax-transgenic Drosophila model, we show that the Urm1-dependent subcellular targeting of Tax is evolutionary conserved, and that the presence of Urm1 is strongly correlated with the transcriptional output of Diptericin, an antimicrobial peptide and established downstream target of NF-κB in flies.
CONCLUSIONS: These data put forward Urm1 as a novel Tax modifier that modulates its oncogenic activity and hence represents a potential novel target for developing new strategies for treating ATL.

Göktuna SI, Diamanti MA, Chau TL
IKKs and tumor cell plasticity.
FEBS J. 2018; 285(12):2161-2181 [PubMed] Related Publications
Nuclear factor κB (NF-κB) transcription factors are the central hubs of signaling pathways connecting proinflammatory signals to cell survival, proliferation and cytokine production. In cancers, NF-κB signaling influences many aspects of tumor development, from initiation to metastasis. These functions are mediated by tumor-induced plasticity that allows tumor cells to adapt and survive in changing conditions within the tumor microenvironment. Tumor cell plasticity is shaped by the inflammatory microenvironment in tumors. This review focuses on inhibitor of NF-κB kinases, the direct upstream elements of NF-κB regulation, specifically on their conventional and non-conventional functions in animal models of tumorigenesis from the recent literature.

Matsumura T, Hida S, Kitazawa M, et al.
Fascin1 suppresses RIG-I-like receptor signaling and interferon-β production by associating with IκB kinase ϵ (IKKϵ) in colon cancer.
J Biol Chem. 2018; 293(17):6326-6336 [PubMed] Free Access to Full Article Related Publications
Fascin1 is an actin-bundling protein involved in cancer cell migration and has recently been shown also to have roles in virus-mediated immune cell responses. Because viral infection has been shown to activate immune cells and to induce interferon-β expression in human cancer cells, we evaluated the effects of fascin1 on virus-dependent signaling via the membrane- and actin-associated protein RIG-I (retinoic acid-inducible gene I) in colon cancer cells. We knocked down fascin1 expression with shRNA retrovirally transduced into a DLD-1 colon cancer and L929 fibroblast-like cell lines and used luciferase reporter assays and co-immunoprecipitation to identify fascin1 targets. We found that intracellular poly(I·C) transfection to mimic viral infection enhances the RIG-I/MDA5 (melanoma differentiation-associated gene 5)-mediated dimerization of interferon regulatory factor 3 (IRF-3). The transfection also significantly increased the expression levels of IRF-7, interferon-β, and interferon-inducible cytokine IP-10 in fascin1-deleted cells compared with controls while significantly suppressing cell growth, migration, and invasion. We also found that fascin1 constitutively interacts with IκB kinase ϵ (IKKϵ) in the RIG-I signaling pathway. In summary, we have identified fascin1 as a suppressor of the RIG-I signaling pathway associating with IκB kinase ϵ in DLD-1 colon cancer cells to suppress immune responses to viral infection.

Xu X, Wang J, Han K, et al.
Antimalarial drug mefloquine inhibits nuclear factor kappa B signaling and induces apoptosis in colorectal cancer cells.
Cancer Sci. 2018; 109(4):1220-1229 [PubMed] Free Access to Full Article Related Publications
Nuclear factor kappa B (NF-κB) signaling pathway is activated in many colorectal cancer (CRC) cells and in the tumor microenvironment, which plays a critical role in cancer initiation, development, and response to therapies. In the present study, we found that the widely used antimalarial drug mefloquine was a NF-κB inhibitor that blocked the activation of IκBα kinase, leading to reduction of IκBα degradation, decrease of p65 phosphorylation, and suppressed expression of NF-κB target genes in CRC cells. We also found that mefloquine induced growth arrest and apoptosis of CRC cells harboring phosphorylated p65 in culture and in mice. Furthermore, expression of constitutive active IKKβ kinase significantly attenuated the cytotoxic effect of the compound. These results showed that mefloquine could exert antitumor action through inhibiting the NF-κB signaling pathway, and indicated that the antimalarial drug might be repurposed for anti-CRC therapy in the clinic as a single agent or in combination with other anticancer drugs.

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