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Experimental Biology and Medicine 233:21-31 (2008)
doi: 10.3181/0707-MR-196
© 2008 Society for Experimental Biology and Medicine

MINIREVIEW

Nuclear Factor-{kappa}B Activation: From Bench to Bedside

Gautam Sethi, Bokyung Sung and Bharat B. Aggarwal1

Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 143, Houston, Texas 77030

1 To whom requests for reprints should be addressed at Bharat B. Aggarwal, Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 143, Houston, TX 77030. Email: aggarwal{at}mdanderson.org


   Abstract
Top
 Abstract
Introduction
 Role of NF-{kappa}B in...
 Constitutive Activation of NF...
 Mechanisms of Constitutive NF...
 How to Suppress NF-{kappa}B...
 Perspectives
 References
 
Nuclear factor-{kappa}B (NF-{kappa}B) is a proinflammatory transcription factor that has emerged as an important player in the development and progression of malignant cancers. NF-{kappa}B targets genes that promote tumor cell proliferation, survival, metastasis, inflammation, invasion, and angiogenesis. Constitutive or aberrant activation of NF-{kappa} is frequently encountered in many human tumors and is associated with a resistant phenotype and poor prognosis. The mechanism of such persistent NF-{kappa}B activation is not clear but may involve defects in signaling pathways, mutations, or chromosomal rearrangements. Suppression of constitutive NF-{kappa}B activation inhibits the oncogenic potential of transformed cells and thus makes NF-{kappa}B an interesting new therapeutic target in cancer.

Key Words: NF-{kappa}B • cancer • IKK • metastasis • invasion


   Introduction
Top
 Abstract
 Introduction
Role of NF-{kappa}B in...
 Constitutive Activation of NF...
 Mechanisms of Constitutive NF...
 How to Suppress NF-{kappa}B...
 Perspectives
 References
 
Nuclear factor-{kappa}B (NF-{kappa}B) is a nuclear transcription factor that was first identified in 1986 by Sen and Baltimore (1). It was so named because it was found in the nucleus bound to an enhancer element of the immunoglobulin kappa light chain gene in B cells (1, 2). It was initially considered to be a B-cell–specific transcription factor but was later shown to be present in every cell type. The Rel/NF-{kappa}B transcription factor family is composed of several structurally related proteins that exist in organisms ranging from insects to humans. The vertebrate family includes five cellular proteins: c-Rel, Rel A, RelB, p50/p105, and p52/ p100. These proteins can form homodimers or heterodimers that give diverse combinations of dimeric complexes, which in turn bind to DNA target sites known as {kappa}B sites, where they directly regulate gene expression. A commonly known NF-{kappa}B consists of a p50/RelA heterodimer (RelA is also referred to as p65). The different Rel/NF-{kappa}B proteins show a distinct ability to form dimers, distinct preferences for different {kappa}B sites, and distinct abilities to bind to inhibitory subunits known as I{kappa}Bs (3). Thus, different Rel/NF-{kappa}B complexes can be induced in different cell types and, by means of distinct signals, interact in distinct ways with other transcription factors and regulatory proteins to regulate the expression of distinct gene sets.

I{kappa}Bs bind to NF-{kappa}B dimers and sterically block their nuclear localization sequences, thereby causing their cytoplasmic retention. Most agents that activate NF-{kappa}B mediate the phosphorylation-induced degradation of I{kappa}B. Upon receiving a signal, I{kappa}B{alpha} is phosphorylated at two conserved serine residues (S32 and S36) in its N-terminal regulatory domain. Several well-characterized I{kappa}B kinase (IKK) complexes consist of IKK{alpha} and β serving as kinases and IKK{gamma} functioning as a regulatory subunit. Once phosphorylated and while still bound to NF-{kappa}B, I{kappa}Bs almost immediately undergo a second post-translational modification called polyubiquitination. The major ubiquitin acceptor sites in human I{kappa}B{alpha} are lysines 21 and 22. Protein ubiquitination occurs through E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme, and E3 ubiquitin protein ligases. After ubiquitination, I{kappa}Bs are degraded in 26S proteasomes, leading to the release of NF-{kappa}B dimers that translocate into the nucleus (4).

Activation of NF-{kappa}B is a tightly regulated event. In normal cells, NF-{kappa}B becomes activated only after the appropriate stimulation and then, and then, upregulates the transcription of its target genes. NF-{kappa}B is activated by many divergent stimuli, including proinflammatory cytokines such as tumor necrosis factor-{alpha} (TNF-{alpha}), interleukin-1β (IL-1β), epidermal growth factor (EGF), T- and B-cell mitogens, bacteria and lipopolysaccharides (LPS), viruses, viral proteins, double-stranded RNA, and physical and chemical stresses (5). Cellular stresses such as ionizing radiation and chemotherapeutic agents also activate NF-{kappa}B (6). One of the first genes that NF-{kappa}B activates is I{kappa}B{alpha} itself, which transports activated NF-{kappa}B from the nucleus to the cytoplasm. NF-{kappa}B activation is therefore an inducible but transient event in normal cells. In tumor cells, different types of molecular alterations may result in impaired regulation of NF-{kappa}B activation. In such cases, NF-{kappa}B loses its transient nature of activation and becomes constitutively activated. This leads to deregulated expression of NF-{kappa}B–controlled genes.


   Role of NF-{kappa}B in Cancer
Top
 Abstract
 Introduction
 Role of NF-{kappa}B in...
Constitutive Activation of NF...
 Mechanisms of Constitutive NF...
 How to Suppress NF-{kappa}B...
 Perspectives
 References
 
NF-{kappa} has been implicated in carcinogenesis because of its critical roles in cell survival, cell adhesion, inflammation, differentiation, and cell growth (7). The role of NF-{kappa}B in different steps of tumorigenesis is discussed below.

NF-{kappa}B Activation Is Required for Cell Proliferation.
Several genes that mediate cell proliferation are regulated by NF-{kappa}B. These include growth factors such as TNF-{alpha}, IL-1β, and interleukin-6 (IL-6) (3). For instance, TNF has been shown to be a growth factor for glioblastoma (8, 13) and cutaneous T-cell lymphoma (9); IL-1β, a growth factor for acute myelogenous leukemia (10); and IL-6, a growth factor for multiple myeloma (11) and head and neck squamous cell carcinoma (12). Besides growth factors, certain cell cycle-regulatory proteins (eg, the cyclin D1 required for transition of cells from G1 to S phase) are also regulated by NF-{kappa}B (13).

In some cells, PGE2 has been shown to induce proliferation of tumor cells. The synthesis of cyclooxygenase-2 (COX-2), which controls PGE2 production, is also regulated by NF-{kappa}B activation (14). It has also been shown that growth factors such as EGF and platelet-derived growth factor (PDGF) induce proliferation of tumor cells through activation of NF-{kappa}B (15, 16). We have recently shown that the EGF receptor activates NF-{kappa}B through tyrosine phosphorylation of I{kappa}B{alpha} at residue 42 in lung cancer cells (17). NF-{kappa}B signaling has also been shown to promote both cell survival and neurite process formation in nerve growth factor–stimulated PC12 cells (18).

Activation of NF-{kappa}B Promotes Survival of Tumor Cells.
Several gene products that negatively regulate apoptosis in tumor cells are controlled by NF-{kappa}B activation. These include IAP-1, IAP-2, XIAP, cFLIP, TRAF1, TRAF2, Bcl-2, Bcl-xL, A1, and survivin (3). Bcl-xL suppresses the release of cytochrome C from the mitochondria, IAPs inhibit caspase-3 and caspase-9 (19), and FLIP inhibits caspase-8(20). NF-{kappa}B has been linked to anti-apoptotic function in tumors such as T-cell lymphoma, melanoma, pancreatic cancer, bladder cancer, and breast cancer and in tumor-related cell types such as B cells, T cells, granulocytes, macrophages, neuronal cells, smooth muscle cells, and osteoclasts (1).

NF-{kappa}B Mediates the Invasion of Tumor Cells.
Several proteases that influence tumor invasiveness (eg, the matrix metalloproteinases and the serine protease urokinase-type plasminogen activator [uPA]) are reportedly regulated by NF-{kappa}B (21, 22). Matrix metalloproteinases (MMPs) promote growth of cancer cells through the interaction of extracellular matrix (ECM) molecules and integrins, cleaving insulin-like growth factors and shedding transmembrane precursors of growth factors, including transforming growth factor-β (TGF-β). MMPs promote angiogenesis by increasing the bioavailability of proangiogenic growth factors. MMPs also regulate invasion and migration by degrading structural ECM components, in particular, by cleaving laminin-5.

uPA is another critical protease involved in tumor invasion and metastasis. Novak et al. reported that transcriptional activation of the uPA gene by phorbol 12-myristate 13-acetate (PMA), IL-1β, and TNF-{alpha} requires the induction of NF-{kappa}B activity and the decay of its short-lived repressor protein, I{kappa}B{alpha}. The uPA promoter contains an NF-{kappa}B binding site that directly mediates the induction of uPA expression by RelA. Recent studies have further shown that constitutively active phosphatidylinositol-3 kinase (PI3K) controls cell motility by regulating the expression of uPA through the activation of NF-{kappa}B (22). Thus, one potential way to block the invasion of tumors is to target NF-{kappa}B and thus its activation of genes involved in cancer progression.

NF-{kappa}B Activation Is Needed for Angiogenesis.
It is now well recognized that angiogenesis is critical for tumor progression and that this process is dependent on chemokines (eg, MCP-1, IL-8) and growth factors (eg, vascular endothelial growth factor [VEGF]) produced by neutrophils and other inflammatory cells (23). The production of these angiogenic factors has been shown to be regulated by NF-{kappa}B activation (23). NF-{kappa}B has been shown to mediate the up-regulation of IL-8 and VEGF expression in bombesin-stimulated PC-3 cells (24). Yu et al. demonstrated that NF-{kappa}B expression was associated with VEGF expression and microvessel density in human colorectal cancer (25). In another study, Pollet et al. demonstrated that LPS directly stimulated endothelial sprouting via TRAF6 in vitro and that inhibition of NF-{kappa}B activity downstream from TRAF6 was sufficient to inhibit LPS-induced endothelial sprouting (26). Also, inhibition of NF-{kappa}B activity blocked basic fibroblast growth factor (bFGF)–induced angiogenesis. These studies further establish the role of NF-{kappa}B activation in angiogenesis.

NF-{kappa}B Is Involved in Tumor Cell Metastasis.
The metastasis of cancer requires the migration of cancerous cells both into and out of the vessel walls that transport them to other parts of the body. The ability to penetrate through vessel walls is mediated by specific molecules that are expressed on the endothelial cells of the blood vessels in response to a number of signals from inflammatory cells, tumor cells, etc. Among those special molecules are ICAM-1, ELAM-1, and VCAM-1, all of which have been shown to be expressed in response to NF-{kappa}B activation (27). Helbig et al. have demonstrated that NF-{kappa}B can regulate the motility of breast cancer cells by directly upregulating the expression of CXCR4 (28). These results implicate NF-{kappa}B in the migration and organ-specific homing of metastatic breast cancer cells. These studies demonstrate the importance of suppressing NF-{kappa}B activation in reducing the metastasis of cancer cells to other sites.


   Constitutive Activation of NF-{kappa}B in Cancer
Top
 Abstract
 Introduction
 Role of NF-{kappa}B in...
 Constitutive Activation of NF...
Mechanisms of Constitutive NF...
 How to Suppress NF-{kappa}B...
 Perspectives
 References
 
There is now considerable evidence that sustained or constitutive activation of NF-{kappa}B is prevalent in cell lines (Table 1Go) (29–71, 132) and that this contributes to malignant progression and therapeutic resistance in most of the major human cancers. As explained above, the activation of NF-{kappa}B occurs as it is transported from the cytoplasm to the nucleus upon degradation of the inhibitory subunit. In the nucleus, NF-{kappa}B binds to specific B sites on the DNA and mediates the expression of a number of genes involved in the cellular response to various stresses. Thus, when NF-{kappa}B is found to persist in the nucleus, it is referred to as constitutive activation. NF-{kappa}B is constitutively activated in human lymphomas (45) and in carcinomas of the breast (32), prostate (65), lung (72), colon (73), pancreas (62), head and neck (44, 74), and esophagus (75).


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  		Table 1. Constitutive Nuclear Factor-{kappa}B Activation in Human Cell Lines
 
The precise role of constitutive activation in tumors is not known but has been linked to resistance to apoptosis in human cutaneous T-cell lymphoma cells (9). It is tempting to believe that a similar mechanism accounts for the progression of all tumors that constitutively express NF-{kappa}B, but such a link has yet to be clearly identified. Normally, activation of NF-{kappa}B has been shown to be stimulus dependent, such that some stimuli such as TNF-{alpha} cause its activation in certain cells whereas other stimuli such as IL-1 or hypoxia cause its activation in other cells. While many NF-{kappa}B stimuli have been identified, the stimulus responsible for constitutive activation of NF-{kappa}B in most cell types is not understood. Cells that express constitutively activated NF-{kappa}B are resistant to various chemotherapeutic agents and radiation treatment. While the precise mechanism leading to induction of chemoresistance and radioresistance is not clear, these examples make the development of inhibitors to NF-{kappa}B more promising and attractive.

Besides cell lines, activated NF-{kappa}B has also been noted in tissue samples derived from patients (Table 2Go) (25, 74–94). For instance, NF-{kappa}B is constitutively activated in high-grade squamous intraepithelial lesions and squamous cell carcinomas of the human uterine cervix (95). NF-{kappa}B has been implicated in an aggressive phenotype of renal cell carcinoma (RCC). Out of 45 cases of RCC, 33% showed > 200% higher NF-{kappa}B activity than did normal renal tissue. In locally advanced cases, 64% showed increased activity. Tissue from metastases showed an even greater increase in NF-{kappa}B activity. Serum C-reactive protein (CRP) elevation correlated with the increase in NF-{kappa}B activation; therefore, NF-{kappa}B may be a cause of the inflammatory paraneoplastic syndrome (96). Yu et al. reported that increased expression of NF-{kappa}B in colorectal tumorigenesis plays an important role in the pathogenesis of colon cancer in humans by mediating the transition from colorectal adenoma with low-grade dysplasia to adenocarcinoma (25).


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  		Table 2. Constitutive Nuclear Factor-{kappa}B Activation in Tumor Samples from Patients
 

   Mechanisms of Constitutive NF-{kappa}B Activation
Top
 Abstract
 Introduction
 Role of NF-{kappa}B in...
 Constitutive Activation of NF...
 Mechanisms of Constitutive NF...
How to Suppress NF-{kappa}B...
 Perspectives
 References
 
Why and how tumor cells express constitutively active NF-{kappa}B is not fully understood, however, several mechanisms have been proposed, as described in Table 3Go, (9, 64, 87, 91, 97–121).


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  		Table 3. Mechanisms of Constitutive Nuclear Factor-{kappa}B Activation in Tumor Cells
 
Some possible explanatory mechanisms include aberrant IKK activity and a shorter I{kappa}B{alpha} half-life (as seen in B-cell lymphoma), I{kappa}B{alpha} mutation (as seen in Hodgkin lymphoma), IL-1β production (as seen in AML), and TNF-{alpha} production (as seen in cutaneous T-cell lymphoma and Burkitt lymphoma). There have been reports of autocrine or paracrine activation of NF-{kappa}B resulting from overexpression of ligands and receptors of epidermal growth factor(17), HER-2/neu (101), TNF-{alpha} (9), interleukin-1 (122), hepatocyte growth factor (123), and integrins (124). Epidermal growth factor receptor and HER-2/neu signaling involving PI3K, IKK, and CK2 has been demonstrated in breast cancer (125); hepatocyte growth factor/PI3K/Pak/ IKK signaling in prostate carcinoma (123); and NF-{kappa}B activation via persistent IKK activation in colon carcinomas, mantle cell lymphoma, and melanomas (Fig. 1Go) (48, 55, 126).


Figure 1
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  		Figure 1.
 
The BCR-ABL fusion oncogene has also been implicated in NF-{kappa}B activation, cell survival, and tumorigenesis in human leukemias (100). Activation by a translocation that produces a MALT-1 fusion protein has been reported in diffuse large B-cell lymphomas (127). Constitutive activation of NF-{kappa}Bp52:p52 due to overexpression and association with the transactivating family member Bcl-3 has been detected in breast carcinomas and lymphomas (30, 128). Direct mutation or altered expression of NF-{kappa}B molecules has only rarely been found in human cancers and in Hodgkin lymphomas, where mutations of I{kappa}B{alpha} that favor activation have been identified (129).

Aman et al. recently reported an association between transglutaminase (TG2) overexpression and constitutive activation of NF-{kappa}B in various types of cancer cells. They found that inhibition of TG2 activity by synthetic inhibitors or small interfering RNA (siRNA) inhibits the constitutive activation of NF-{kappa}B. Moreover, they observed a direct association between TG2 and the I{kappa}B{alpha} /p65:p50 complex and cross-linked forms of I{kappa}B{alpha} in TG2-expressing cells. Immunohistochemical analysis of pancreatic ductal carcinoma samples obtained from patients further supported a strong correlation between TG2 expression and NF-{kappa}B activation (35).

Our group recently found for the first time that a TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-{kappa}B activation and proliferation in human head and neck squamous cell carcinoma (44). In head and neck squamous cell cancer (HNSCC) cells, constitutive NF-{kappa}B activation has been seen in association with autocrine expression of TNF, TNF receptors, and receptor-activators of NF-{kappa}B and its ligand but not with autocrine expression of IL-1β . Furthermore, treatment of HNSCC cells with anti-TNF antibody downregulated the expression of constitutively active NF-{kappa}B and was associated with inhibition of IL-6 expression and cell proliferation.

Lastly, many viruses achieve their oncogenic effects via the NF-{kappa}B signaling cascade. A notable example relevant to human cancer is the human T-cell leukemia virus-1 (HTLV-1) implicated in acute T-cell leukemia (ATL). Persistent activation of NF-{kappa}B by HTLV-1 Tax causes nuclear accumulation of NF-{kappa}B dimers, helps to overcome their inhibition by the p105/ NF-{kappa}B1subunit, and is an essential step in the transformation of T cells (130). Additionally, Tax stimulates phosphorylation-dependent processing of NF-{kappa}B2/p100 and hence activates both the canonical and noncanonical NF-{kappa}B pathways (131). Another virus that contributes to human cancer via NF-{kappa}B is the Epstein-Barr virus (EBV) implicated in Burkitt’s and Hodgkin’s lymphomas. The EBV nuclear antigen (EBNA)-2 and latent membrane protein (LMP)-1 enhance NF-{kappa}B activity thereby preventing apoptosis in EBV-transformed B cells (119).


   How to Suppress NF-{kappa}B Activation?
Top
 Abstract
 Introduction
 Role of NF-{kappa}B in...
 Constitutive Activation of NF...
 Mechanisms of Constitutive NF...
 How to Suppress NF-{kappa}B...
Perspectives
 References
 
NF-{kappa}B is an ideal target for anticancer drug development (132). Cancer is a hyperproliferative disorder that involves transformation, initiation, promotion, angiogenesis, invasion, and metastasis. The diversity of its clinical presentation, aggressiveness, and current treatment strategies implies an equally diverse number of potential targets in the molecular pathways leading to its formation. Several strategies have been employed to block the activation of NF-{kappa}B. A wide variety of compounds (eg, IKK inhibitors, inhibitory peptides, antisense RNA, proteasome inhibitors, chemopreventive agents) have been screened for their ability to suppress NF-{kappa}B.

Proteasome Inhibitors Block NF-{kappa}B Activation.
Proteasome inhibitors block the 26S proteasome necessary to degrade the I{kappa}B{alpha} inhibitory subunit after its phosphorylation and ubiquitination in the cytoplasm and thus its release from the NF-{kappa}B complex (133). Some of the other well-known proteasome inhibitors are peptide aldehydes such as ALLnL, LLM, Z-LLnV, and Z-LLL, lactacystine, PS-341, N-cbz-Leu-Leu-leucinal (MG132), MG115, and ubiquitin ligase inhibitors (134). Recently, our group described a novel proteasome inhibitor known as Salinosporamide A (also called NPI-0052) that suppressed both constitutive and inducible NF-{kappa}B activation in low nanomolar range (135). Some serine protease inhibitors also act as proteasome inhibitors and block the phosphorylation and degradation of I{kappa}B{alpha} (136).

Inhibitors of IKK Block NF-{kappa}B Activation.
I{kappa}B{alpha} phosphorylation is a critical step in NF-{kappa}B activation, and compounds that block this phosphorylation prevent NF-{kappa}B’s ubiquitination and further degradation. Recently, the lipid peroxidation product known as 4-hydroxy-2-nonenal has been shown to block phosphorylation by direct inhibition of IKK (137). Also, we recently reported that butein, a natural product derived from the stem bark of cashews, directly inhibits IKK activity by modulating cysteine residue at position 179 (138).

Acetylation Inhibitors Can Block NF-{kappa}B Activation.
Histone acetylation modulates gene expression, cellular differentiation, and survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Acetylation of RelA is not only required for transactivation but also prevents nucleocytoplasmic trafficking of NF-{kappa}B (139). The histone deacetylase HDAC3 acts directly upon nuclear RelA to enable its association with I{kappa}B{alpha} and its subsequent export from the nucleus. HDAC3 is another potential target for gene transfer. Expression of HDAC3 in TNF-stimulated HeLa cells repressed both NF-{kappa}B DNA-binding and levels of RelA with a corresponding increase in inactive cytoplasmic I{kappa}B{alpha}-NF-{kappa}B complexes (140). This mechanism was shown to control the duration of NF-{kappa}B activation and thus may be a potential weapon against constitutive NF-{kappa}B activation.

Gene Transfer of Inhibitory Proteins Can Block NF-{kappa}B Activation.
Transfer of genes that encode inhibitory proteins is another strategy used to block the activation of NF-{kappa}B. The most direct target is the I{kappa}B gene. In brief, this entails the modification of I{kappa}B at the specific phosphorylation sites (Ser 32 and 36 switched with Ala) and at ubiquitination sites (Lys 21 and 22 switched with Arg) so as to prevent its degradation. In several studies, this super-repressor of NF-{kappa}B activity was a mutated nondegradable I{kappa}B{alpha} resistant to phosphorylation and degradation that could be delivered into intestinal epithelial cells (IEC) via an adenoviral vector (Ad5 I{kappa}B). Inhibition of NF-{kappa}B activity was strong because the super-repressor kept the NF-{kappa}B complex in the cytoplasm indefinitely (141). These studies suggest an exciting approach to in vivo intestinal gene therapy and illustrate a key role for NF-{kappa}B in transcriptional regulation of the inflammatory phenotype of IEC. Recently, a non-phosphorylatable form of I{kappa}B{alpha} was shown to inhibit osteoclastogenesis and block bone resorption when injected into bone marrow macrophages (142).

Antisense RNA and siRNA Can Block NF-{kappa}B Activation.
Antisense agents that inhibit the expression of a target gene in a sequence-specific manner may be used therapeutically against NF-{kappa}B. Three anti-mRNA strategies can be distinguished. The first involves the use of single-stranded antisense oligonucleotides inhibit RNA expression; the second involves the use of catalytically active oligonucleotides (ribozymes) to trigger RNA cleavage; the third involves the application of siRNA molecules. siRNAs have the demonstrated potential to decrease p65 protein expression levels (143). In a study in which siRNAs were directed against IKK{alpha}, IKKβ, and the upstream regulatory kinase TAK1, both IKK{alpha} and IKKβ were found to be important in activating the NF-{kappa}B pathway (144).

Some Peptides Can Cross the Cell Membrane and Block NF-{kappa}B Activation.
Another approach to inhibiting NF-{kappa}B activation is to use peptides that cross the cell membrane and block the nuclear localization of the NF-{kappa}B complex. For example, SN-50 and o,o’-bismyristoyl thiamine disulfide (145) work by mimicking the sequence of p50 normally responsible for transporting the NF-{kappa}B complex from the cytoplasm to the nucleus. Also, a novel peptide that selectively blocks the association of IKK{gamma} (NEMO) with the rest of the IKK complex has been shown to inhibit NF-{kappa}B activation in mice while preserving basal NF-{kappa}B activity (146).

Anti-inflammatory Agents Block NF-{kappa}B Activation.
Additionally, several anti-inflammatory agents capable of suppressing NF-{kappa}B activation have been identified. Examples are aspirin, ibuprofen, indomethacin, tamoxifen, dexamethasone, and sulindac (132). However, their exact mechanism of action in this regard is not fully understood. Ghosh and Kopp demonstrated that the anti-inflammatory drugs sodium salicylate and aspirin inhibited the activation of NF-{kappa}B by preventing the degradation of the NF-{kappa}B inhibitor, I{kappa}B{alpha}, so that NF-{kappa}B was retained in the cytosol (147).

Chemopreventive Agents Inhibit NF-{kappa}B Activation.
Because of NF-{kappa}B’s critical role in tumor proliferation, invasion, angiogenesis, and metastasis, there has been great interest in agents that can modulate the NF-{kappa}B signaling pathway. Several agents, which have been described as natural chemopreventive agents, have also been found to be potent inhibitors of constitutive NF-{kappa}B activation. These include curcumin, resveratrol, guggulsterone, evodiamine, indole-3 carbinol, 1'-acetoxychavicol acetate, acetyl-11-keto-β-boswellic acid, plumbagin, with-anolide, celastrol, embelin, and gossypin (148–150). For instance, curcumin has been shown to suppress the constitutive NF-{kappa}B activation in multiple myeloma (11) and in pancreatic cancer (151) through the downregulation of constitutively active IKK. Whether other chemopreventive agents also act via the same mechanism is not clear. The inhibition of NF-{kappa}B with the methods illustrated above represents possible approaches to the more complicated issue of creating drug therapies that are effective in preventing or attenuating tumorigenesis. An understanding of their precise mechanisms of action, specificity, and even toxicity with respect to NF-{kappa}B is still incomplete. However, targeting NF-{kappa}B is central to designing an effective therapy for cancer.


   Perspectives
Top
 Abstract
 Introduction
 Role of NF-{kappa}B in...
 Constitutive Activation of NF...
 Mechanisms of Constitutive NF...
 How to Suppress NF-{kappa}B...
 Perspectives
References
 
Constitutive activation of NF-{kappa}B is an emerging hallmark of various types of tumors. Many experimental models in vitro and in animals indicate NF-{kappa}B’s role in the regulation of apoptosis, as well as tumor angiogenesis, proliferation, invasion, and metastasis. The enhanced activation of NF-{kappa}B in tumors appears to be mainly due to dysregulation of upstream kinases, mutations in I{kappa}B{alpha}, and viral infections. The importance of NF-{kappa}B in tumor progression is evident in many recent studies utilizing various inhibitors of NF-{kappa}B for the treatment of cancer. The use of NF-{kappa}B inhibitors has resulted in significant antitumor effects in tumor xenograft models and led, in some cases, to ongoing clinical trials. It is important to note, however, that therapeutically targeting NF-{kappa}B in cancers will require optimization of both drug design and drug delivery in patients.


   Footnotes
 
Dr. Aggarwal is the Ransom Horne, Jr., Professor of Cancer Research. This work was supported by a grant from the Clayton Foundation for Research (to B.B.A.) and National Institutes of Health PO1 grant CA91844 on lung chemoprevention (to B.B.A).


   References
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 Abstract
 Introduction
 Role of NF-{kappa}B in...
 Constitutive Activation of NF...
 Mechanisms of Constitutive NF...
 How to Suppress NF-{kappa}B...
 Perspectives
 References
 

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