Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Constitutive nuclear factor-kappaB (NF-kappaB) activity plays a crucial role in the development and progression of lymphoma, leukemia, and some epithelial cancers. Given the contribution of NF-kappaB in carcinogenesis, a novel approach that interferes with its activity might have therapeutic potential against cancers that respond poorly to conventional treatments. Here, we have shown that a new IkappaB kinase beta inhibitor, IMD-0354, suppressed the growth of human breast cancer cells, MDA-MB-231, HMC1-8, and MCF-7, by arresting cell cycle and inducing apoptosis. In an electrophoretic mobility shift assay and a reporter assay, IMD-0354 abolished the NF-kappaB activity in MDA-MB-231 cells in a dose-dependent manner. In the cells incubated with IMD-0354, cell cycle arrested at the G0-G1 phase and apoptotic cells were increased. The expression of some cell cycle regulatory molecules and antiapoptotic molecules was suppressed in cells treated with IMD-0354. On the other hand, cyclin-dependent kinase suppressor p27Kip1 was up-regulated by the addition of IMD-0354. Daily administration of IMD-0354 inhibited tumor expansion in immunodeficient mice into which MDA-MB-231 cells were transplanted. These results indicate that NF-kappaB may contribute to cell proliferation through up-regulation of cell cycle progression; accordingly, inhibition of NF-kappaB activity might have a therapeutic ability in the treatment of human breast cancers.
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PMID:A new IkappaB kinase beta inhibitor prevents human breast cancer progression through negative regulation of cell cycle transition. 1639 57

Aberrant expression of cyclooxygenase-2 (COX-2) has been implicated in tumor promotion. Resveratrol, a phytoalexin present in grapes, was reported to inhibit multistage mouse skin carcinogenesis. In the present study, we found that topically applied resveratrol significantly inhibited COX-2 expression induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Resveratrol-suppressed phosphorylation and subsequent degradation of IkappaBalpha, thereby inhibiting activation of nuclear factor-kappaB (NF-kappaB) in TPA-stimulated mouse skin. Pretreatment with resveratrol also suppressed TPA-induced phosphorylation of extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein (MAP) kinase. Resveratrol blunted TPA-induced phosphorylation of p65 and its interaction with CBP/p300, rendering NF-kappaB transcriptionally inactive. To get further insights into the molecular basis of NF-kappaB inactivation by resveratrol, we examined the role of IkappaB kinase (IKK) in mediating TPA-induced activation of NF-kappaB and COX-2 expression. TPA treatment led to rapid induction of IKK activity in mouse skin, which was abolished either by resveratrol or an IKK inhibitor Bay 11-7082. Topical application of Bay 11-7082 also abrogated TPA-induced NF-kappaB activation and COX-2 expression, supporting the involvement of IKK in TPA-induced COX-2 expression. Taken together, the above findings suggest that resveratrol targets IKK in blocking TPA-induced NF-kappaB activation and COX-2 expression in mouse skin in vivo.
Carcinogenesis 2006 Jul
PMID:Resveratrol inhibits phorbol ester-induced expression of COX-2 and activation of NF-kappaB in mouse skin by blocking IkappaB kinase activity. 1647 81

One of the most frequent events in carcinogenesis is uncontrolled activation of Ras signaling pathway. A previous study demonstrated that the introduction of H-Ras into the normal WB-F344 rat liver epithelial (WB) cell line and adult male F344 rats resulted in tumorigenicity. The present study investigated whether H-Ras induced the invasive and migrative phenotypes in WB cells, and subsequently aimed at characterizing the underlying mechanisms. H-Ras induced the invasive and migrative phenotypes of WB cells with a selective up-regulation of matrix metalloproteinase (MMP)-9, but not MMP-2. Cyclooxygenase (COX)-2 and the subsequent production of prostaglandin E2 (PGE2) were also induced by H-Ras. Treatment of H-Ras WB cells with GM6001 and NS398, the inhibitors of MMPs and COX-2, respectively, significantly inhibited the H-Ras-induced invasive and migrative phenotypes. DNA binding activity of nuclear factor (NF)-kappaB, but not that of activator protein (AP)-1, was increased by H-Ras. Caffeic acid phenethyl ester and Bay 11-7082, specific inhibitors of NF-kappaB and IKK, respectively, significantly inhibited the expression of MMP-9 and COX-2, invasion and migration of H-Ras WB cells, revealing NF-kappaB as a transcriptional factor responsible for H-Ras-induced malignant phenotypic conversion of WB cells. Activation of ERKs pathway was critical for H-Ras-induced invasive and migrative phenotypes, up-regulation of MMP-9 and COX-2 as well as enhanced DNA binding activity of NF-kappaB in WB cells. Taken together, these results demonstrate that H-Ras up-regulates MMP-9 and COX-2 through activation of ERKs and IKK-IkappaBalpha-NF-kappaB signal pathway which may contribute to the malignant progression of WB rat liver epithelial cells.
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PMID:H-Ras selectively up-regulates MMP-9 and COX-2 through activation of ERK1/2 and NF-kappaB: an implication for invasive phenotype in rat liver epithelial cells. 1672 10

Activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) triggers cellular signals that lead to the activation of the transcription factor NF-kappaB (nuclear factor kappaB) in various cell types. In addition to NF-kappaB activation by short-time PMA treatment, here we report that the prolonged exposure of human colonic cancer epithelial cells treated with PMA can also lead to a persistent inhibition of NF-kappaB activation. PMA selectively causes the degradation of IkappaB kinases (IKKs) including IKK-gamma and IKK-beta, and subsequent inhibition of tumor necrosis factor (TNF) induced IKK and NF-kappaB activation in human colon cancer cell line HCT-116, but not in other gastrointestinal tract cells. The use of Ro-318220 and GO-6983, general PKC inhibitors as well as MG-132, a proteasome-specific inhibitor, abrogated PMA-induced degradation of IKK-gamma and recovered the activation of IKK by TNF, suggesting that IKK complex is predominantly degraded by the proteasome pathway in a PKC-dependent manner. We also found that IKK-gamma strongly associates with heat shock protein 90 (Hsp90) in HCT-116 cells, and that this interaction was dramatically reduced after exposure to PMA. Furthermore, high levels of Hsp90 expression and enhanced association with IKK were observed in human colon cancer tissues. Taken together, these results suggest that long-term activation of PKC by PMA inhibits NF-kappaB system in case of colon cancer cells by disrupting the interaction of IKK-gamma with Hsp90, which may represent a novel regulatory mechanism of PKC-dependent cellular differentiation and limited proliferation of colonic epithelial cells.
Carcinogenesis 2007 Jan
PMID:Sustained activation of protein kinase C downregulates nuclear factor-kappaB signaling by dissociation of IKK-gamma and Hsp90 complex in human colonic epithelial cells. 1677 32

A major link between inflammation and cancer is provided by NF-kappaB transcription factors. Ikkbeta(Deltahep) mice, which specifically lack IkappaB kinase beta (IKKbeta), an activator of NF-kappaB, in hepatocytes, are unable to activate NF-kappaB in response to proinflammatory stimuli, such as TNF-alpha. Surprisingly, Ikkbeta(Deltahep) mice are hypersusceptible to diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Because defective NF-kappaB activation promotes sustained c-Jun N-terminal kinase (JNK) activation in cells exposed to TNF-alpha, whose expression is induced by DEN, and JNK activity is required for normal hepatocyte proliferation, we examined whether increased susceptibility to DEN-induced hepatocarcinogenesis in Ikkbeta(Deltahep) mice requires JNK activation. Hepatocytes express both JNK1 and JNK2, but previous studies indicate that JNK1 is more important for hepatocyte proliferation. We therefore investigated this hypothesis using mice homozygous for a JNK1 deficiency either in wild-type or Ikkbeta(Deltahep) backgrounds. In both cases, mice lacking JNK1 were much less susceptible to DEN-induced hepatocarcinogenesis. This impaired tumorigenesis correlated with decreased expression of cyclin D and vascular endothelial growth factor, diminished cell proliferation, and reduced tumor neovascularization. Whereas hepatocyte-specific deletion of IKKbeta augmented DEN-induced hepatocyte death and cytokine-driven compensatory proliferation, disruption of JNK1 abrogated this response. In addition to underscoring the importance of JNK1-mediated hepatocyte death and compensatory proliferation, these results strongly suggest that the control of tissue renewal through the IKK and JNK pathways plays a key role in liver carcinogenesis.
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PMID:Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. 1680 93

Benzo[alpha]pyrene-7,8-diol-9,10-epoxide (B[a]PDE), the major metabolite of benzo[a]pyrene (B[a]P), shows an ultimate complete carcinogen in various animals and is a causative agent for human cancers. However, its effects on the activation of signal pathways and the expression of genes involved in its carcinogenic effect remain largely unknown. In this study, the effects of B[a]PDE on induction of cyclooxygenase (COX)-2 and the signal pathways leading to the induction were investigated. Treatment of mouse epidermal Cl41 cells with B[a]PDE caused an increase in the expression of COX-2 at both transcription and protein levels, while its parental compound B[a]P did not show significant inductive effect. The COX-2 induction by B[a]PDE was dependent on the activation of mitogen-activated protein kinases (MAPK)s/activation protein (AP)-1 pathway, because inhibition of AP-1 by either overexpression of TAM67 (dominant negative mutant of c-jun), or pretreatment of cells with PD98059 (MEK1/2-ERKs pathway inhibitor) or SB202190 (p38K inhibitor), markedly inhibited B[a]PDE-induced COX-2 expression. In addition, impairment of NF-kappaB pathway by either NEMO-BDBP (an NF-kappaB specific inhibitor) or IkappaB kinase (IKK)beta-KM (dominant negative mutant of IKKbeta) also caused marked reduction of COX-2 induction by B[a]PDE. In contrast, inhibition of nuclear factor of activated T cells (NFAT) with FK506, did not show any effect on B[a]PDE-induced COX-2 expression. Collectively, these data indicate that exposure of Cl41 cells to B[a]PDE can induce COX-2 expression by increasing its transcription, which requires the activation of MAPKs/AP-1 and IKKbeta/NF-kappaB pathways, but not NFAT pathway. In view of the importance of COX-2 in carcinogenesis, we anticipate that the induction of COX-2 by B[a]PDE may coordinate its mutagenic effects to facilitate the development of skin cancer.
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PMID:Benzo[a]pyrene diol-epoxide (B[a]PDE) upregulates COX-2 expression through MAPKs/AP-1 and IKKbeta/NF-kappaB in mouse epidermal Cl41 cells. 1692 90

Conjugated linoleic acid (CLA) has been reported to inhibit mouse skin carcinogenesis, particularly in the promotion stage, but underlying molecular mechanisms remain poorly understood. Since persistent induction of cyclooxygenase-2 (COX-2) is frequently implicated in carcinogenesis, we investigated the effect of cis-9,trans-11-CLA (9Z,11E-CLA) on the tumor promoter-induced COX-2 expression in HR-1 hairless mouse skin in vivo. Topical application of 9Z,11E-CLA caused significant inhibition of COX-2 expression at 6 h induced by 10 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) in HR-1 mouse skin. Since NF-kappaB is known to regulate COX-2 gene expression, we determined the effect of 9Z,11E-CLA on TPA-induced activation of this transcription factor. Treatment of mouse skin with 9Z,11E-CLA reduced TPA-induced DNA binding as well as nuclear translocation of NF-kappaB by blocking phosphorylation and subsequent degradation of IkappaBalpha. In addition, 9Z,11E-CLA attenuated TPA-induced phosphorylation of extracellular signal-regulated protein kinase, p38 mitogen-activated protein kinase and Akt. To further elucidate the molecular mechanism underlying the inactivation of NF-kappaB by 9Z,11E-CLA, we investigated its effect on TPA-induced activation of IkappaB kinase (IKK), an upstream kinase that regulates NF-kappaB via phosphorylation and degradation of IkappaBalpha. 9Z,11E-CLA treatment down-regulated phosphorylation and catalytic activities of IKKalpha/beta in TPA-treated mouse skin. Co-treatment of mouse skin with the IKKbeta-specific inhibitor SC-514 (1 micromol) attenuated TPA-induced activation of Akt and NF-kappaB, and also the expression of COX-2 in hairless mouse skin. Taken together, 9Z,11E-CLA inhibits NF-kappaB driven-COX-2 expression by blocking the IKK and PI3K-Akt signaling in TPA-treated hairless mouse skin in vivo, which may account for its previously reported anti-tumor promoting effects.
Carcinogenesis 2007 Feb
PMID:cis-9,trans-11-conjugated linoleic acid down-regulates phorbol ester-induced NF-kappaB activation and subsequent COX-2 expression in hairless mouse skin by targeting IkappaB kinase and PI3K-Akt. 1695 Jul 95

IKK (I kappaB kinase) alpha is essential for embryonic skin development in mice. Mice deficient in IKKalpha display markedly hyperplasic epidermis that lacks terminal differentiation, and they die because of this severely impaired skin. However, the function of IKKalpha in human skin diseases remains largely unknown. To shed light on the role of IKKalpha in human skin diseases, we examined IKKalpha expression and Ikkalpha mutations in human squamous cell carcinomas (SCCs). We found a marked reduction in IKKalpha expression in poorly differentiated human SCCs and identified Ikkalpha mutations in exon 15 of Ikkalpha in eight of nine human SCCs, implying that IKKalpha is involved in development of this human skin cancer. Furthermore, in a chemical carcinogen-induced skin carcinogenesis setting, mice overexpressing human IKKalpha in the epidermis under the control of a truncated loricrin promoter developed significantly fewer SCCs and metastases than did wild-type mice. The IKKalpha transgene altered the skin microenvironment conditions, leading to elevated terminal differentiation in the epidermis, reduced mitogenic activity in the epidermis, and decreased angiogenic activity in the skin stroma. Thus, overexpression of IKKalpha in the epidermis antagonized chemical carcinogen-induced mitogenic and angiogenic activities, repressing tumor progression and metastases.
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PMID:A critical role for I kappaB kinase alpha in the development of human and mouse squamous cell carcinomas. 1707 94

WNT signals are context-dependently transduced to canonical and non-canonical signaling cascades. We cloned and characterized wild-type human WNT10B, while another group cloned aberrant human WNT10B with Gly60Asp amino-acid substitution. Proto-oncogene WNT10B is expressed in gastric cancer, pancreatic cancer, breast cancer, esophageal cancer, and cervical cancer. Because WNT10B blocks adipocyte differentiation, coding SNP of WNT10B gene is associated with familial obesity. In 2001, we reported WNT10B upregulation by TNFalpha. Here, comparative integromics analyses on WNT10B orthologs were performed to elucidate the transcriptional mechanism of WNT10B. Chimpanzee WNT10B and cow Wnt10b genes were identified within NW_001223159.1 and AC150975.2 genome sequences, respectively, by using bioinformatics (Techint) and human intelligence (Humint). Chimpanzee WNT10B and cow Wnt10b showed 98.7% and 95.1% total-amino-acid identity with human WNT10B, respectively. N-terminal signal peptide, 24 Cys residues, two Asn-linked glycosylation sites, and Gly60 of human WNT10B were conserved among mammalian WNT10B orthologs. Transcription start site of human WNT10B gene was 106-bp upstream of NM_003394.2 RefSeq 5'-end. Number of GC di-nucleotide repeats just down-stream of WNT10B transcription start site varied among primates and human population. Comparative genomics analyses revealed that double AP1-binding sites in the 5'-flanking promoter region and NF-kappaB-binding site in intron 3 were conserved among human, chimpanzee, cow, mouse, and rat WNT10B orthologs. Because TNFalpha signaling through TNFR1 and TRADD/RIP/TRAF2 complex activates JUN kinase (JNK) and IkappaB kinase (IKK) signaling cascades, conserved AP1- and NF-kappaB-binding sites explain the mechanism of TNFalpha-induced WNT10B upregulation. TNFalpha-WNT10B signaling loop is the negative feedback mechanism of adipogenesis to prevent obesity and metabolic syndrome. On the other hand, TNFalpha-WNT10B signaling loop is implicated in carcinogenesis. Inhibitors of TNFalpha-WNT10B signaling loop could be utilized for the prevention or treatment of cancer associated with chronic inflammation, such as gastric, liver, breast and pancreatic cancer.
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PMID:AP1- and NF-kappaB-binding sites conserved among mammalian WNT10B orthologs elucidate the TNFalpha-WNT10B signaling loop implicated in carcinogenesis and adipogenesis. 1733 47

Humulone, a bitter acid derived from hop (Humulus lupulus L.), possesses antioxidative, anti-inflammatory and other biologically active activities. Although humulone has been reported to inhibit chemically induced mouse skin tumor promotion, the underlying mechanisms are yet to be elucidated. Since an inappropriate over-expression of cyclooxygenase-2 (COX-2) is implicated in carcinogenesis, we investigated effects of humulone on COX-2 expression in mouse skin stimulated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical application of humulone (10 mumol) significantly inhibited TPA-induced epidermal COX-2 expression. Humulone also diminished TPA-induced DNA binding of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). Pre-treatment with humulone attenuated TPA-induced phosphorylation of p65 and nuclear translocation of NF-kappaB subunit proteins. Humulone blunted TPA-induced activation of inhibitory kappaB (IkappaB) kinase (IKK) in mouse skin, which accounts for its suppression of phosphorylation and subsequent degradation of IkappaBalpha. An in vitro kinase assay revealed that humulone could directly inhibit the catalytic activity of IKKbeta. Humulone suppressed the activation of mitogen-activated protein kinases (MAPKs) in TPA-treated mouse skin. The roles of extracellular signal-regulated protein kinase-1/2 and p38 MAPK in TPA-induced activation of NF-kappaB in mouse skin had been defined in our previous studies. The present study revealed that topical application of SP600125, a pharmacological inhibitor of c-Jun-N-terminal kinase (JNK), abrogated the activation of AP-1 and the expression of COX-2 in TPA-treated mouse skin. Taken together, humulone suppressed TPA-induced activation of NF-kappaB and AP-1 and subsequent expression of COX-2 by blocking upstream kinases IKK and JNK, respectively, which may account for its antitumor-promoting effects on mouse skin carcinogenesis.
Carcinogenesis 2007 Jul
PMID:Humulone inhibits phorbol ester-induced COX-2 expression in mouse skin by blocking activation of NF-kappaB and AP-1: IkappaB kinase and c-Jun-N-terminal kinase as respective potential upstream targets. 1737 74


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