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)

Nuclear factor kappaB (NF-kappaB) has been implicated in inducible chemoresistance against anthracyclines. In an effort to improve the cytotoxicity of anthracyclines while reducing their cardiotoxic effects, we have developed a novel class of extranuclear-localizing 14-O-acylanthracyclines that bind to the phorbol ester/diacylglycerol-binding C1b domain of conventional and novel protein kinase C (PKC) isoforms, thereby promoting an apoptotic response. Because PKCs have been shown to be involved in NF-kappaB activation, in this report, we determined the mechanism of NF-kappaB activation by N-benzyladriamycin-14-valerate (AD 198) and N-benzyladriamycin-14-pivalate (AD 445), two novel 14-O-acylanthracylines. We show that the induction of NF-kappaB activity in response to drug treatment relies on the activation of PKC-delta and NF-kappaB-activating kinase (NAK), independent of ataxia telengectasia mutated and p53 activities. In turn, NAK activates the IKK complex through phosphorylation of the IKK-2 subunit. We find that neither NF-kappaB activation nor ectopic expression of Bcl-X(L) confers protection from AD 198-induced cell killing. Overall, our data indicate that activation of novel PKC isoforms by cytoplasmic-targeted 14-O-acylanthracyclines promotes an apoptotic response independent of DNA damage, which is unimpeded by inducible activation of NF-kappaB.
 ...
PMID:Circumvention of nuclear factor kappaB-induced chemoresistance by cytoplasmic-targeted anthracyclines. 1504 34

Nuclear factor-kappaB (NF-kappaB) plays a critical role during fetal liver development and hepatic oncogenesis. Here, we have assessed whether NF-kappaB activity is required for murine hepatocellular carcinoma cell survival. We show that adenoviral-mediated inhibition of inhibitor of NF-kappaB kinase-beta (IKK-2) activity in hepatocellular carcinomas derived from transforming growth factor (TGF)-alpha/c-myc bitransgenic mice leads to inhibition of NF-kappaB and promotes tumor necrosis factor (TNF)-alpha-mediated cell death of malignant hepatocytes but not the surrounding peritumorous tissue. Induction of apoptosis is accompanied by inhibition of Bcl-X(L) and XIAP, two pro-survival NF-kappaB target genes. In addition, we have identified the alpha-fetoprotein (AFP) as a novel downstream target of NF-kappaB. We show that repression of IKK-2 activity in hepatocellular carcinomas promotes down-regulation of AFP gene expression. Likewise, genetic disruption of the RelA subunit results in reduced AFP gene expression during embryonic liver development, at a time in which fetal hepatocytes are sensitized to TNF-alpha-mediated cell killing. In this regard, we show that AFP inhibits TNF-alpha-induced cell death of murine hepatocellular carcinomas through association with TNF-alpha and inhibition of TNFRI signaling. Thus, NF-kappaB-mediated regulation of AFP gene expression during liver tumor formation and embryonic development of the liver constitutes a potential novel mechanism used by malignant and fetal hepatocytes to evade immune surveillance.
 ...
PMID:Regulation of alpha-fetoprotein by nuclear factor-kappaB protects hepatocytes from tumor necrosis factor-alpha cytotoxicity during fetal liver development and hepatic oncogenesis. 1546 96

Recent studies indicate that natural isothiocyanates, such as sulforaphane (SFN) and phenethyl isothiocyanate (PEITC) possess strong antitumor activities in vitro and in vivo. The nuclear factor kappa B (NF-kappaB) is believed to play an important role in cancer chemoprevention due to its involvement in tumor cell growth, proliferation, angiogenesis, invasion, apoptosis, and survival. In this study, we investigated the effects and the molecular mechanisms of SFN and PEITC on NF-kappaB transcriptional activation and NF-kappaB-regulated gene expression in human prostate cancer PC-3 C4 cells. Treatment with SFN (20 and 30 microM) and PEITC (5 and 7.5 microM) significantly inhibited NF-kappaB transcriptional activity, nuclear transloction of p65, and gene expression of NF-kappaB-regulated VEGF, cylcin D1, and Bcl-X(L) in PC-3 C4 cells. To further elucidate the mechanism, we utilized the dominant-negative mutant of inhibitor of NF-kappaB alpha (IkappaBalpha) (SR-IkappaBalpha). Analogous to treatments with SFN and PEITC, SR-IkappaBalpha also strongly inhibited NF-kappaB transcriptional activity as well as VEGF, cylcin D1, and Bcl-X(L) expression. Furthermore, SFN and PEITC also inhibited the basal and UVC-induced phosphorylation of IkappaBalpha and blocked UVC-induced IkappaBalpha degradation in PC-3 C4 cells. In examining the upstream signaling, we found that the dominant-negative mutant of IKKbeta (dnIKKbeta) possessed inhibitory effects similar to SFN and PEITC on NF-kappaB, VEGF, cylcin D1, Bcl-X(L) as well as IkappaBalpha phosphorylation. In addition, treatment with SFN and PEITC potently inhibited phosphorylation of both IKKbeta and IKKalpha and significantly inhibited the in vitro phosphorylation of IkappaBalpha mediated by IKKbeta. Taken together, these results suggest that the inhibition of SFN and PEITC on NF-kappaB transcriptional activation as well as NF-kappaB-regulated VEGF, cyclin D1, and Bcl-X(L) gene expression is mainly mediated through the inhibition of IKK phosphorylation, particularly IKKbeta, and the inhibition of IkappaBalpha phosphorylation and degradation, as well as the decrease of nuclear translocation of p65 in PC-3 cells.
 ...
PMID:Suppression of NF-kappaB and NF-kappaB-regulated gene expression by sulforaphane and PEITC through IkappaBalpha, IKK pathway in human prostate cancer PC-3 cells. 1585 23

NF-kappaB is constitutively activated in adult T-cell leukemia (ATL) and is considered responsible for cell growth and prevention of cell death. In this study, we demonstrate that NF-kappaB is constitutively activated in various HTLV-1-infected T-cell lines and ATL-derived cell lines irrespectively of Tax expression as evidenced by the phosphorylation of IkappaBalpha and p65 subunit of NF-kappaB, activation of NF-kappaB DNA binding, and upregulation of various target genes including bcl-xL, bcl-2, XIAP, c-IAP1, survivin, cyclinD1, ICAM-1 and VCAM-1. The effects of a novel IkappaB kinase (IKK) inhibitor, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile (ACHP), were examined on cell growth of these cell lines and fresh ATL leukemic cells. We found that ACHP could inhibit the phosphorylation of IkappaBalpha and p65, as well as NF-kappaB DNA-binding, associated with downregulation of the NF-kappaB target genes and induce cell growth arrest and apoptosis in these cells. When Tax-active and Tax-inactive cell lines were compared, ACHP could preferentially inhibit cell growth of Tax-active cells. Moreover, ACHP exhibited strong apoptosis-inducing activity in fresh ATL cells. These findings indicate that ACHP and its derivatives are effective in inducing ATL cell death and thus feasible candidates for the treatment of ATL.
 ...
PMID:Induction of cell death in adult T-cell leukemia cells by a novel IkappaB kinase inhibitor. 1645 1

While fruits and vegetables are recommended for prevention of cancer and other diseases, their active ingredients (at the molecular level) and their mechanisms of action less well understood. Extensive research during the last half century has identified various molecular targets that can potentially be used not only for the prevention of cancer but also for treatment. However, lack of success with targeted monotherapy resulting from bypass mechanisms has forced researchers to employ either combination therapy or agents that interfere with multiple cell-signaling pathways. In this review, we present evidence that numerous agents identified from fruits and vegetables can interfere with several cell-signaling pathways. The agents include curcumin (turmeric), resveratrol (red grapes, peanuts and berries), genistein (soybean), diallyl sulfide (allium), S-allyl cysteine (allium), allicin (garlic), lycopene (tomato), capsaicin (red chilli), diosgenin (fenugreek), 6-gingerol (ginger), ellagic acid (pomegranate), ursolic acid (apple, pears, prunes), silymarin (milk thistle), anethol (anise, camphor, and fennel), catechins (green tea), eugenol (cloves), indole-3-carbinol (cruciferous vegetables), limonene (citrus fruits), beta carotene (carrots), and dietary fiber. For instance, the cell-signaling pathways inhibited by curcumin alone include NF-kappaB, AP-1, STAT3, Akt, Bcl-2, Bcl-X(L), caspases, PARP, IKK, EGFR, HER2, JNK, MAPK, COX2, and 5-LOX. The active principle identified in fruit and vegetables and the molecular targets modulated may be the basis for how these dietary agents not only prevent but also treat cancer and other diseases. This work reaffirms what Hippocrates said 25 centuries ago, let food be thy medicine and medicine be thy food.
 ...
PMID:Molecular targets of dietary agents for prevention and therapy of cancer. 1656 57

Nuclear factor-kappaB (NF-kappaB), a transcription factor with a critical role in promoting inflammation and cell survival, is constitutively activated in estrogen-receptor (ER)-negative breast cancer and is considered a potential therapeutic target for this type of neoplasia. We have previously demonstrated that cyclopentenone prostaglandins are potent inhibitors of NF-kappaB activation by inflammatory cytokines, mitogens, and viral infection, via direct binding and modification of the beta subunit of the IkappaB kinase complex (IKK). Herein, we describe the NF-kappaB-dependent anticancer activity of natural and synthetic cyclopentenone IKK inhibitors. We demonstrate that the natural cyclopentenone 15-deoxy-Delta(12,14)prostaglandin J(2) (15d-PGJ(2)) is a potent inhibitor of constitutive IkappaB-kinase and NF-kappaB activities in chemotherapy-resistant ER-negative breast cancer cells. 15d-PGJ(2)-induced inhibition of NF-kappaB function is rapidly followed by down-regulation of NF-kappaB-dependent antiapoptotic proteins cIAPs 1/2, Bcl-X(L), and cellular FLICE-inhibitory protein, leading to caspase activation and induction of apoptosis in breast cancer cells resistant to treatment with paclitaxel and doxorubicin. We then demonstrate that the cyclopentenone ring structure is responsible for these activities, and we identify a new synthetic cyclopentenone derivative, 3-tert-butyldimethylsilyloxy-5-(E)-iso-propylmethylenecyclopent-2-enone (CTC-35), as a potent NF-kappaB inhibitor with proapoptotic activity in ER-negative breast cancer cells. The results open new perspectives in the search for novel proapoptotic molecules effective in the treatment of cancers presenting aberrant NF-kappaB regulation.
 ...
PMID:Induction of apoptosis in estrogen receptor-negative breast cancer cells by natural and synthetic cyclopentenones: role of the IkappaB kinase/nuclear factor-kappaB pathway. 1690 99

We recently reported that bcl-xL regulates interleukin 8 (CXCL8) protein expression and promoter activity in glioblastoma cells. In this paper we demonstrate that CXCL8 induction by bcl-xL is mediated through a nuclear factor-kappa B (NF-kB)-dependent mechanism. Mutational studies on the CXCL8 promoter showed that NF-kB binding site was required for bcl-xL-induced promoter activity and an enhanced nuclear expression of NF-kB subunits p65 and p50 was observed after bcl-xL over-expression. Electrophoretic mobility shift assay showed an increased DNA-binding activity of NF-kB in bcl-xL over-expressing cells and the use of specific antibodies confirmed the involvement of p65 and p50 in NF-kB activity on CXCL8 promoter sequence. NF-kB activity regulation by bcl-xL involved IkBalpha and IKK complex signaling pathway. In fact, bcl-xL over-expression induced a decrease of cytoplasmic expression of the IkBalpha protein, paralleled by an increase in the phosphorylation of the same IkBalpha and IKKalpha/beta. Moreover, the down-regulation of the ectopic or endogenous bcl-xL expression through RNA interference confirmed the ability of bcl-xL to modulate NF-kB pathway, and the transient expression of a degradation-resistant form of the cytoplasmic NF-kB inhibitor IkBalpha in bcl-xL transfectants confirmed the involvement of that inhibitor in bcl-xL-induced CXCL8 expression and promoter activity. In conclusion, our results demonstrate the role of NF-kB as the mediator of bcl-xL-induced CXCL8 up-regulation in glioblastoma cells.
 ...
PMID:Involvement of nuclear factor-kappa B in bcl-xL-induced interleukin 8 expression in glioblastoma. 1878 78

Based on Bcl-X(L) overexpression studies we identified type I and type II follicular lymphoma cell lines in response to TRAIL. We demonstrate here that either amount of caspase-8 activation or Bid cleavage could not define the dependence on mitochondria. Furthermore, an inhibitor of NF-kappaB, PDTC, enabled TRAIL to activate type I apoptotic pathway in type II cells. However, an inhibitor of IKK did not switch apoptosis to type I pathway in type II cells, indicating that NF-kappaB might not be responsible for the switch.
 ...
PMID:PDTC enables type I TRAIL signaling in type II follicular lymphoma cells. 1897 30

The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. A complementary strategy for targeting KRAS is to identify gene products that, when inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkappaB kinase TBK1 was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappaB anti-apoptotic signals involving c-Rel and BCL-XL (also known as BCL2L1) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations indicate that TBK1 and NF-kappaB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.
 ...
PMID:Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. 1989 Mar 18

One of the features of malignant gliomas is their deviant resistance to cellular apoptosis induced by cytotoxic reagents. Bmi-1, an oncoprotein, has been linked to oncogenesis and cancer progression in various types of human cancers including gliomas. However, the mechanisms underlying Bmi-1 antiapoptotic function remain largely unknown. In this study, we report that Bmi-1 renders apoptotic resistance to glioma cells through nuclear factor-kappaB (NF-kappaB). In glioma cells, ectopic expression of Bmi-1 significantly inhibits doxorubicin-, BCNU-, or UV irradiation- induced apoptosis through reduction of activated caspase-3 and PARP, and induction of Bcl-X(L). Cellular depletion of Bmi-1 enhances the sensitivity of glioma cells to apoptosis induced by doxorubicin, BCNU, or UV irradiation. Bmi-1 activates NF-kappaB through stimulation of IkappaB phosphorylation, nuclear translocation, and transcriptional activity of NF-kappaB and expression of downstream genes of NF-kappaB including caspase-3, PARP, Bcl-X(L), and c-Myc. Inhibition of the IKK-NF-kappaB pathway abrogates the antiapoptotic effect of Bmi-1 on glioma cells. In high-grade gliomas, Bmi-1 and NF-kappaB are co-expressed in the cell nucleus. Up-regulation of Bmi-1 also correlates with tumor progression and poor survival of patients with gliomas. Together, our data demonstrate that Bmi-1 bestows apoptotic resistance to glioma cells through the IKK-NF-kappaB pathway and suggest Bmi-1 as a useful indicator for glioma prognosis.
 ...
PMID:Oncoprotein Bmi-1 renders apoptotic resistance to glioma cells through activation of the IKK-nuclear factor-kappaB Pathway. 2003 51


1 2 Next >>