1. ABSTRACT

Lung cancer ranks as the first malignant tumor killer worldwide. Despite the knowledge that carcinogens from tobacco smoke and the environment constitute the main causes of lung cancer, the mechanisms for lung carcinogenesis are still elusive. Cancer development and progression depend on the balance between cell survival and death signals. Common cell survival signaling pathways are activated by carcinogens as well as by inflammatory cytokines, which contribute substantially to cancer development. As a major cell survival signal, nuclear factor-kappaB (NF-kappaB) is involved in multiple steps in carcinogenesis and in cancer cell's resistance to chemo- and radio-therapy. Recent studies with animal models and cell culture systems have established the links between NF-kappaB and lung carcinogenesis, highlighting the significance of targeting NF-kappa signaling pathway for lung cancer treatment and chemoprevention. In this review, we summarize progresses in understanding the NF-kappaB pathway in lung cancer development as well as in modulating NF-kappaB for lung cancer prevention and therapy.

2. INTRODUCTION

Lung cancer is the leading cause of cancer-related death, which afflicts approximately 170,000 people each year in the United States (1). A large number of lung cancers are associated with cigarette smoke, although other factors such as environmental influences like radon or nutrition may be also involved (2). Many lung cancer patients are diagnosed at late stages of the disease when surgery is not applicable. Chemotherapy and radiation therapy, as well as a combination of both therapies, are used in an attempt to reduce tumor mass and halt disease progression. However, because such therapies are usually ineffective for lung cancer, the prognosis of the patients is usually very poor (3). Therefore, development of effective prevention and therapy approaches against lung cancer is critical for reducing mortality.

Cancer cells, including lung cancer cells, have acquired numerous characteristic alterations facilitating their oncogenic growth. Accumulating evidence suggests that lung cancer cells use multiple and perhaps redundant pathways to maintain survival (2). Common signal transduction pathways for cell survival and proliferation include mitogen-activated protein kinases (MAPK), Akt and NF-kappaB. In lung cancer cells, multiple mechanisms are used to override or "hijack" the signal transduction pathways to facilitate their own survival and proliferation (4). In this review, we will summarize the recent reports on NF-kappaB in lung cancer biology and discuss the preventive and therapeutic potential of targeting NF-kappaB against lung cancer.

3. NF-KAPPAB ACTIVATION PATHWAYS

3.1. Protein components in the NF-kappaB family

In mammalian cells, five NF-kappaB family members are found: p65 (RelA), RelB, c-Rel, p50/p105 (NF-kappaB1) and p52/p100 (NF-kappaB2). These proteins share a unique N-terminal Rel homology domain (RHD) for forming hetero- or homodimer dimmers and binding DNA. Having a C-terminal transactivation domain (TAD) p65, RelB, and c-Rel function as transactivators when associated with p50 or p52, while p50 and p52 lack TADs, and their homodimers serve as transcription repressors that provide a threshold for NF-kappaB activation (5). The most common form of NF-kappaB is a heterodimer consisting of p65 and p50. In most quiescent normal cells the NF-kappaB dimers are bound with and kept in the cytoplasm by inhibitor of kappaBs (IkappaBs) that mask the nuclear localization sequence (NLS) in the NF-kappaB proteins. Five members of the IkappaB protein family have been identified so far: IkappaBalpha, IkappaBbeta, IkappaBgamma, IkappaBepsilon and BCL-3. The high affinity of IkappaB proteins in binding NF-kappaB ensures the activation of this pathway in a tight check. The precursor proteins p105 and p100 function similarly as the IkappaB proteins to squelch NF-kappaB in the cytoplasm (5).

3.2. The pathways leading to NF-kappaB activation

As a multifunctional transcription factor, NF-kappaB is activated by numerous extracellular stimuli including cytokines, growth factors, carcinogens and tumor promoters and intracellular cues ignited by genotoxic or endoreticulum stress (ER stress). There are three pathways leading to NF-kappaB activation and ultimately to expression of distinct sets of target genes for diverse biological functions (Fig. 1) (6).,

Being the major NF-kappaB activation pathway in most cell types, the canonical pathway involves dimers composed of p50 and p65 or c-Rel (5) and is often activated by microbial infections, growth factors and proinflammatory cytokines including TNFalpha. TNFalpha engagement induces trimerization of TNFalpha receptor 1 (TNFR1) and recruitment of multiple adaptor proteins and kinases, resulting in the phosphorylation and activation of IkappaB kinase (IKK) complex. IKKs consist of catalytic subunits IKKalpha/IKK1, IKKbeta/IKK2, and an essential regulatory subunit IKKgamma/nuclear factor-kappaB essential modulator (NEMO). The IKK activity is solely dependent on IKKbeta for the canonical pathway, and the IKK activating kinase is thought to be mitogen activated kinase 3 (MEKK3) or TGFbeta-activated kinase 1 (TAK1) (7-9). The activated IKK is switched from the TNFR1 signaling complex to the NF-kappaB/IkappaB complex, where IKKbeta phosphorylates the serine 32 and 36 in IkappaB, which is then polyubiquitinated followed by rapid degradation in the proteasome. When NF-kappaB is freed up from IkappaB, the NLS signal on p65 and p50 is exposed, leading to nuclear translocation of NF-kappaB. In the nucleus, NF-kappaB is subjected to further modifications including phosphorylation and acetylation on the p65 subunit, which impact the locating in the compartments in the nucleus (10), binding to DNA or interaction with transcriptional co-activators such as cAMP response element-binding protein (CBP)/p300 (5).

DNA damage induced by anticancer genotoxic agents and ionizing radiation activates the IKK-IkappaB-NF-kappaB cascade, which is also regarded as a canonical pathway. DNA damage rapidly induces the ataxia telangiectasia mutated (ATM) kinase, which phosphorylates the IKK subunit NEMO/IKKgamma in a complex in the nucleus called PIDDsome, consisting of RIP1, p53-induced death domain (PIDD) and NEMO (11). After a serial modification including phosphorylation and sumolysation, NEMO migrates from the nucleus to the cytoplasm to bind and activate IKKbeta. Then IKKbeta phosphorylates IkappaB and turns on the canonical NF-kappaB activation pathway (12). IKKepsilon is involved in modification of p65 in the nucleus to modulate the DNA damage-induced NF-kappaB activation (13).

The noncanonical pathway involves the non-death receptor members of the TNF receptor family such as CD40, lymphotoxin beta (LTbeta) and B-cell-activating factor (BAF). When these receptors are activated by their cognate ligands, NF-kappaB inducing kinase (NIK) is stabilized and activated, presumably by auto-phosphorylation, which mediates IKKalpha phosphorylation. Subsequently, IKKalpha triggers conformation change in p100, which is then cleaved to generate p52. A functional NF-kappaB heterodimer containing p52 and RelB is formed and translocated to the nucleus to turn on gene expression (5). The c-IAP proteins that are required for activating the canonical pathways, suppress the noncanonical pathway through NIK ubiquitination and degradation (6, 14). Therefore, the canonical and noncanonical pathways are coordinated under some circumstances, which may provide a delicate control of the overall NF-kappaB activity in the cell. The non-canonical NF-kappaB pathway is activated by K-Ras^G12D through TANK-binding kinase 1 (TBK1), contributing to oncogenic K-Ras-mediated lung carcinogenesis (15).

The atypical pathways lead to NF-kappaB activation by distinct mechanisms. For example, casein kinase 2 (CK2) rather than IKK is required for short wavelength ultraviolet (UV) light -induced NF-kappaB activation. In this pathway, calpain rather than proteasome is involved in IkappaB degradation (16). Also, it is reported that phosphorylation of IkappaB at Tyr42 by c-Src or Syk kinases underlies the mechanism for hydrogen peroxide-induced NF-kappaB activation (17).

4. NF-KAPPAB'S CELLULAR FUNCTIONS

4.1. NF-kappaB and transcription

NF-kappaB is a transcription factor that induces expression of more than 200 genes involved in diverse process such as cell survival, cell adhesion, inflammation, differentiation and growth (5). Activation of NF-kappaB up-regulates expression of its responsive genes in cancer cells including lung cancer cells (18, 19). However, under certain conditions, NF-kappaB can function as a transcriptional suppressor. For example, DNA-damage-induced NF-kappaB suppresses rather than activates gene transcription (20), which may involve interactions with transcriptional repressors or tumor suppressors such as p53 and ARF (21). Thus, it is important to elucidate the transcriptional functions of DNA damaging anticancer drugs-induced NF-kappaB activation in different cancer cells before applying NF-kappaB manipulating approaches for sensitizing anticancer chemotherapy.

4.2. NF-kappaB and cell proliferation

NF-kappaB is a positive mediator of cell growth and proliferation. NF-kappaB increases the expression of several factors involved in cell cycle progression such as cyclins D and E. Up-regulation of cyclin D1 expression by NF-kappaB is associated with enhanced transition from G1 to S phase. Furthermore, NF-kappaB negatively regulates expression of growth arrest and DNA damage-inducible protein 45 (GADD45), a cell cycle checkpoint protein that keeps cell at the G2/M phase transition (22). Additionally, the mutual interplay between NF-kappaB and proinflammatory cytokines such as TNFalpha and IL1beta is also involved in stimulating cancer cell proliferation, particularly during chronic inflammation (23). However, a potential proliferation suppressing function of NF-kappaB is also proposed, because it suppresses c-Jun N-terminal kinase (JNK), an important proliferation signal in some cell types, and triggers expression of the G1 arrest factor p21/WAF1 (6).

4.3. NF-kappaB and apoptosis

NF-kappaB plays a critical role in blocking apoptosis through various mechanisms, of which induction of antiapoptotic protein expression is regarded as the major one. The NF-kappaB-responsive anti-apoptotic genes include Bcl-XL, cIAP1, cIAP2, XIAP, A20, TRAF-2 and c-FLIP, which promote cell survival by desensitizing the cells to apoptosis induced by a variety of stimuli such as cytokines and chemotherapeutics (24). Second, NF-kappaB can suppress cellular stress-mediated apoptosis through removal of reactive oxygen species (ROS) via increasing expression of manganese superoxide dismutase (MnSOD) (25, 26). Thus, NF-kappaB inhibits both the mitochondrial (intrinsic) and death receptor (extrinsic) pathways. Third, NF-kappaB also negatively regulates the apoptotic JNK activation (27). In addition, NF-kappaB suppresses apoptosis through antagonizing p53, possibly through competition for transcriptional co-activators (28). Finally, NF-kappaB down-regulates the expression of phosphatase and tensin homolog (PTEN) to activate Akt to promote cell survival and proliferation (29).

5. NF-KAPPAB IN LUNG CARCINOGENESIS

5.1. NF-kappaB activation in lung cancer

There is considerable evidence that NF-kappaB is constitutively activated in a variety of solid tumors, including prostate, breast, cervical, pancreatic and lung cancer (30, 31). Although lung tumors are histologically heterogenic, tumor samples obtained from lung cancer patients showed high levels of NF-kappaB activation in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), and is significantly associated with disease advancement in TNM stages and poor prognosis in lung cancer patients (31, 32). Inhibiting NF-kappaB with different approaches such as siRNA, IKK inhibitors and IkappaB super suppressor inhibited lung cancer cell's survival and proliferation (18, 33, 34).

5.1.1. Oncogene-mediated NF-kappaB activation

The contributions of NF-kappaB to lung cancer development are complex, underlying mechanisms of which have not been fully understood. The findings that NF-kappaB activation is associated with K-Ras mutation led to the hypothesis that activation of NF-kappaB is the result of oncogene activation (15, 35, 36). Notably, K-Ras accounts for 90% of Ras mutation in lung cancer. Lose of p53 function and constitutively active K-Ras^G12D collaboratively activate NF-kappaB in lung cancer cells, which is demonstrated in a mouse lung cancer model and in human lung cancer tissues and cell lines (37). K-Ras^G12D also activates the non-canonical NF-kappaB activation pathway through TBK1, and suppression of TBK1 induced apoptosis specifically in human cancer cell lines that have oncogenic K-Ras expression (15).

5.1.2. Inflammation-associated NF-kappaB activation

A large body of evidence suggests that inflammation plays an important role in lung cancer development (38). In addition to pulmonary infection and allergies, cigarette smoke (CS) is a common cause of chronic lung inflammation (38, 39). Myeloid cells (mainly macrophages) are the major source of inflammatory cytokines for cancer promotion and progression. NF-kappaB is a major signal in mediating cytokine synthesis and secretion from myeloid cells. Thus, it is suggested that NF-kappaB in myeloid cells promotes lung cancer mainly through mediating inflammatory cytokines secretion to establish a cancer-prone inflammatory microenvironment (40). Indeed, blocking NF-kappaB in myeloid cells significantly reduced CS-induced pulmonary cytokines and chemokines such as TNFalpha, CCL2, CCL3 and IL-6, and inflammatory cell infiltration, which is associated with reduction of lung tumor multiplicity and tumor size (35, 37). In addition, NF-kappaB in epithelial cells also plays a lung cancer-promoting role (35).

5.1.3. Carcinogen-induced NF-kappaB activation

NF-kappaB can be activated by cigarette smoke (CS) and its components such as nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific carcinogen, in a panel of NSCLC cell lines (41). Because NF-kappaB is persistently activated by CS in the lung epithelial cells far before tumor formation, it is likely that this cell survival signal promotes mutant cells to proliferate and to escape apoptosis in the early phase of lung cancer development (35, 42). In vitro studies have suggested a positive role for NF-kappaB in cell transformation in prostate and colon epithelial cells, fibroblasts, and lymphocytes (6). It remains to be determined if NF-kappaB is also required for lung epithelial cell transformation.

5.1.4. Other NF-kappaB activation mechanisms

The crosstalk between NF-kappaB and the PI3K-Akt-mTOR pathway may also contribute to lung cancer cell survival and proliferation (41). It was shown that PI3K/Akt activates NF-kappaB activity in an IKKalpha-dependent manner (43). Fas-associated death domain protein (FADD) phosphorylation induces an IKK-mediated NF-kappaB activation and proliferation in lung adenocarcinoma, which is significantly associated with poor survival of the patients (44). Furthermore, some growth factor receptors can mediate atypical NF-kappaB activation. Epidermal growth factor (EGF) induces IKK-independent NF-kappaB activation through phosphorylation of the tyrosine residue at the position of 42 in IkappaBalpha in non-small cell lung adenocarcinoma cells (45).

5.2. A lung tumor-promoting role of NF-kappaB in animal models

Due to the complexity of carcinogenesis and the roles of NF-kappaB in different cell types, i.e., immune and parenchymal cells, NF-kappaB exerts controversial effects in different tumor models, strongly suggesting that NF-kappaB's roles in carcinogenesis are cell-, tissue-, or carcinogen-specific (46, 47). For example, opposite roles of NF-kappaB, an anti-tumor role in hepatocytes (parenchymal cells) while a pro-tumor role in Kupffer cells (myeloid cells in liver), were observed in hepatocellular carcinoma development(47). Recent studies with lung cancer mouse models have established NF-kappaB's tumor promoting role in lung carcinogenesis.

In an ethyl carbamate (urethane)-induced prototypical mouse model of multistage lung carcinogenesis in FVB or BALB/c mice, early NF-kappaB activation in airway epithelium, type II alveolar epithelial cells and macrophages was observed. When NF-kappaB was specifically blocked in airway epithelial cells, urethane-induced lung inflammation was inhibited and tumor formation was significantly reduced, which was associated with marked reduction of Bcl-2 expression and increased apoptosis in airway epithelial cells (48).

Appealing evidence showing NF-kappaB's tumor promoting role in lung carcinogenesis was recently reported with a repetitive exposure to CS that promotes tumor development both in carcinogen-treated mice and in transgenic mice undergoing sporadic K-ras activation in lung epithelial cells. Blocking NF-kappaB in either myeloid or epithelial cells by deletion of IKKbeta dramatically inhibited CS-induced pulmonary inflammation and lung tumor multiplicity, suggesting NF-kappaB in either myeloid or epithelial cells promotes lung cancer (35, 40). Consistent with these observations, concomitant loss of p53 and expression of oncogenic K-Ras^G12D caused NF-kappaB activation in primary mouse embryonic fibroblasts, and inhibition of NF-kappaB significantly reduced lung tumor development caused by these genetic mutations (37). Another mouse model with knockout of tumor suppressor gene Gpre5a also showed that NF-kappaB in lung epithelial cells contributes to lung tumor formation (49). These experiments with genetically engineered mouse models demonstrate NF-kappaB's lung tumor-promoting role, pointing to novel approaches for lung cancer therapy and chemoprevention by targeting NF-kappaB (40).

5.3. NF-kappaB in lung tumor angiogenesis and metastasis

Angiogenesis is a process of new blood vessel formation, which is closely associated with cancer development and metastasis. NF-kappaB in inflammatory cells activates secretion of a variety of angiogenesis factors such as vascular endothelial growth factor (VEGF), TNFalpha, IL-8, IL-6, monocyte chemotactic protein-1 (MCP-1), and matrix metalloproteinases (MMPs) (6, 50, 51). NF-kappaB also induces stromal cell-derived factor 1 alpha (SDF-1alpha) to enhance tumor angiogenesis (52). NF-kappaB is involved in beta-arrestin-2-mediated angiogenesis through activation of CXCR2 (53). However, there is evidence showing an inhibitory role of NF-kappaB in tumor angiogenesis (54). Since inhibition of angiogenesis is one important approach in cancer therapy, such findings suggest that caution should be taken when blocking NF-kappaB is used for sensitizing cancer chemotherapy.

Through regulating factors involved in cell migration and adhesion, NF-kappaB stimulates cancer cell metastasis. These factors include MMPs, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), chemokine receptor CXCR4, and serine protease urokinase-type plasminogen activator (uPA) (6, 51). NF-kappaB is involved in upregulation of Twist-1-mediated epithelial-mesenchymal transition (EMT) that is critical for cancer cell invasion and metastasis (55). TGF-beta activates PI3K/Akt-mediated NF-kappaB activation, contributing to the migration of human lung cancer cells. Blocking NF-kappaB activity down-regulates MMP-2 and MMP-9 expressions, resulting in suppression of lung cancer invasion (56). SDF-1 was found to increase invasiveness of A549 cells through activation of ERK/NF-kappaB signaling, which is responsible for the increase of MMP-9 expression of the cells (57).

6. TARGETING NF-KAPPAB SIGNALING FOR LUNG CANCER THERAPY

Systemic chemotherapy, alone or combined with radiation, is used to treat advanced and metastatic lung cancer to improve the survival rate and quality of life of patients. The standard regimen is platinum-based doublets (cisplatin or carboplatin plus other cytotoxic agents). Unfortunately, the prognosis of advanced lung cancer is dismal, partially due to the fact that current chemotherapy for lung cancer has reached an efficacy plateau (58). Thus, new approaches are urgently needed to improve the outcome of treatment.

Besides NF-kappaB is constitutively activated in a variety of cancers, both chemotherapeutics and radiation induce NF-kappaB activation in cancer cells, which contributes to resistance to these therapies (59). For example, commonly used cytotoxic agents such as gemcitabline, paclitaxel, vinblastine and adriamycin, are NF-kappaB inducers (60). Thus, it is assumed that blockage of NF-kappaB will increase the efficacy of anticancer therapeutics. Indeed, inhibition of NF-kappaB signaling with various approaches has been shown to augment the efficacy of chemotherapeutics and radiation in killing cancer cells in vitro and in vivo(61, 62).

6. 1. Agents that inhibit NF-kappaB activation in lung cancer cells

NF-kappaB-inhibiting compounds suppress this pathway directly or indirectly. The direct inhibition involves targeting various components/steps in the NF-kappaB activation pathways such as activation of IKK, degradation of IkappaBalpha, nuclear translocation and DNA binding of NF-kappaB (6, 62). Among these targets, IKK was thought to be the most effective and selective drug target (63). Indirect NF-kappaB inhibition blocks proteins that are not components of, but can activate, NF-kappaB activation pathways.

6.1.1. Proteosome inhibitors

These include bortezomib and other proteosome inhibitors such as MG132 and proteosome inhibitor 1 (PS1) (64, 65). Bortezomib is the first drug in this category approved by FDA for cancer therapy. Proteosome inhibitors block the NF-kappaB pathway through suppression of proteosomal degradation of IkappaB. Prereatment of lung cancer cells with proteasome inhibitors suppressed TNF, TRAIL or irradiation-induced NF-kB activation (101, 103). Randomized phase I and phase II trials in advanced NSCLC show that Bortezomib as a monotherapy has limited activity in lung cancer. Combined with cytotoxic agents or other targeted agents such as erlotinib, bortezomib was well tolerated, but had modest or insufficient activity (66-69). Therefore, the future of bortezomib in treating lung cancer is still uncertain. It should be pointed out that proteasome inhibitors are not NF-kB-specific and anti-cancer effects other than inhibition of NF-kB can also be involved.

6.1.2. Non-steroidal anti-inflammatory drugs (NSAID) and other approved drugs

NSAIDs are anti-inflammatory drugs act through inhibition of COX-1 and -2. Aspirin and sodium salicylate are able to inhibit NF-kappaB activation by suppressing IKKbeta activity (70). Sulindac, a NSAID that has preventive activity against colon cancer, is also an IKKbeta inhibitor that enhances TNF-induced apoptosis in lung cancer cells by inhibiting NF-kappaB nuclear translocation and DNA binding(71). The selective COX-2 inhibitor Celecoxib suppresses cigarette-smoke condensate (CSC)-induced NF-kappaB activation through blocking phosphorylation and degradation of IkappaBalpha and phosphorylation and nuclear translocation of NF-kappaB, resulting in abrogation of CSC's up-regulation of NF-kappaB target genes, Cyclin D1, COX-2 and MMP-9 (72). Sulfasalazine has been shown to inhibit TNFalpha- or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced and IKK-mediated NF-kappaB activation (73). Sulfasalazine reduces NF-kappaB activity and cell invasion, and enhance doxorubicin-induced apoptosis in a series of cell lines from a NSCLC patient (74). Thalidomide inhibits TNF-induced IKK phosphorylation, p65 phosphorylation and nuclear translocation and binding to the ICAM-1 promoter, resulting in down-regulation of ICAM-1 expression and subsequent inhibition of cancer cell's invasiveness in vitro and metastasis in vivo (75). Unfortunately, Phase II and III trials failed to show any survival advantage using thalidomide in combination of standard chemotherapy in treatment of stage III and IV lung cancer (58). Nifedipine, a calcium channel blocker commonly used to treat hypertension, inhibits NF-kappaB in lung cancer cells and macrophages induced by IL-1beta, TNFalpha and TPA (76). Nifedipine exerts its NF-kappaB inhibiting activity by suppressing IKK-mediated IkappaBalpha degradation, subsequently suppressing MMP-9 expression and activity (77, 78).

6.1.3. Natural products and their synthetic derivatives

Dietary components from fruits and vegetables such as polyphenols, terpene, alkaloids and phenolics have proapoptotic, anti-proliferation, anti-angeogenic and anti-metastatic functions. Typically, these compounds show inhibitory activity on multiple signal pathways. NF-kappaB is one of the most frequent targets of these compounds (79). Dietary compounds reported to have NF-kappaB suppression function in lung cancer cells include resveratrol and its analogs, curcumin and its derivative EF24 (3,5-bis(2-flurobenzylidene)piperidin-4-one), (-)-epigallocatechin-3-gallate, genistein, luteolin, silibinin, deguelin, gallic acid, parthenolide, flavopiridol，anthocyanin, quinoclamine and dehydroxymethylepoxyquinomicin (80, 81). Studies have found that crude extracts from strawberry, deerberry, pomegranate fruit and potato sprouts have NF-kappaB suppression activity (82, 83).

Another group of natural products shown to inhibit NF-kappaB activation in lung cancer cells comes from medicinal plants. These include Triptolide purified from Chinese herb Tripterygium wilfordii (84), zyflamend from a polyherbal preparation (85), herbal mixture PS-SPES (86), coix seed extract (87), usolic acid from medical plant (88), embelia from Embelia ribes plant (89), methysticin from Kava (90), phenanthrene-based tylophorine (from Tylophora genus) synthetic derivatives (91). Nature products generally have low toxicity to normal tissues and can simultaneously block several pathways that promote carcinogenesis, making them potential agents for lung cancer therapy and prevention.

6.1.4. Other NF-kappaB inhibitors

The lipid peroxidation product 4-hydroxy-2-nonenal inhibits IKK by covalent modification of the enzymes and subsequently suppresses phosphorylation and degradation of IkappaBalpha in H1299 lung cancer cells (92). The synthetic retinoid N-(4-Hydroxyphenyl) retinamide suppresses TNF-induced NF-kappaB activation and invasion in H1299 cells (93). The histone deacetylase inhibitor suberorylanilide hydroxamic acid (SAHA) was shown to suppress NF-kappaB activation in NSCLC cells and to inhibit growth of A549 xerografts in athymic nude mice through down-regulating TNFR1 protein expression (94).

Other NF-kappaB inhibitors in development include RNA aptamer that targets NF-kappaB (p50) using adevnovirus delivery system. This aptamer was shown to inhibit NF-kappaB activation in A549 cells in vitro and the A549-derived xenografted tumor growth in vivo, and sensitize the cells to doxorubicin's killing (95).

6.1.5. Indirect inhibition of NF-kappaB activation

The tumor suppressor p53 and NF-kappaB have reciprocal inhibitory activity (62). Antagonizing p53 function by NF-kappaB contributes to chemoresistance in cancer cells (96). In A549 cells, the potent MDM2 inhibitor nutlin-3 simultaneously increases the expression of p53 and represses the expression of TNF-induced NF-kappaB target genes ICAM-1 and MCP-1 in a promoter specific manner. Consequently, combined treatment of nultin-3 and TNF reduced cell viability. The mechanism is not clear, because the processes of NF-kappaB signaling are not affected by nultin-3 (97).

Aurora kinases (aurora-A, B and C) are serine/threonine kinases that function in mitosis. Aurora-A is overexpressed in several types of cancer, and has been linked to breast and ovarian tumorigenesis (98, 99). Aurora-A activates NF-kappaB through phosphorylation of IkappaBalpha. Inhibiting Aurora-A suppressed NF-kappaB activity in A549 cells and sensitized the cells to cytotoxicity induced by cisplatin, adriamycin and epotoside (100).

Heat shock protein 90 (Hsp90) is a chaperone that stabilizes a variety of proteins including RIP1 and IKKbeta, two key components of TNFalpha-induced NF-kappaB activation pathway. The Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) targeted RIP1 and IKKbeta for degradation and thus suppressed TNFalpha-induced NF-kappaB activation. Pretreatment with 17-AAG augmented TNFalpha and TNF-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity in lung cancer cells (33).

6.2. Hope and possible benefits of inhibiting NF-kappaB in lung cancer therapy

Since the discovery of inhibition of NF-kappaB can sensitize anticancer chemotherapy, tremendous efforts have been made to develop NF-kappaB inhibitors with a high expectation that these inhibitors will be eventually used as single or adjuvant agent for cancer treatment. Below is a summary, with focus on lung cancer, of the major goals that can be achieved by inhibiting NF-kappaB pathway.

6.2.1. Sensitization of cancer cells to apoptosis inducing therapeutic agents

Some of the NF-kappaB inhibitors that enhance lung cancer cell death induced by chemotherapeutics and ionizing radiation are listed in Table 1.

6.2.2. Inhibition of cancer invasion and metastasis

Blockage of NF-kappaB activation by a dominant negative IkappaBalpha mutant resulted in suppression of tumor cell intravasation in vivo and lung metastasis in a mouse model (111). Of note, chemoresistance of lung cancer cells is associated with metastatic capability. For example, overexpression of AXL, a receptor tyrosine kinase that activates NF-kappaB, induces invasiveness and resistance to doxorubicin. Inhibition of NF-kappaB signaling suppressed tumor cell invasion while synergized the cells to doxorubicin (74). Further, adhesion of SCLC cells to stromal cells protects the cells from etoposide-induced apoptosis (112). Cyanidin-3-glucoside, an anthocyanin isolated from blackberry that is an antioxidant and acts as an inhibitor of several pathways including NF-kappaB, suppresses migration and invasion of A549 cells in vitro and in vivo (113). Inhibition of the NF-kappaB/MMP-9 cascade by (-)-epigallocatechin-3-gallate also suppresses invasion in a highly metastatic human lung cancer cell line in vitro (114). Radiotherapy-induced MMP-9 expression and lung metastasis of Lewis lung cancer cells was also blocked by the NF-kappaB inhibitor arenic trioxide, (115). These studies emphasize the importance of NF-kappaB activation in lung cancer cell metastasis.

6.2.3. Amelioration of malignant pleural effusion

Malignant pleural effusion (MPE) is a severe complication of cancer. Lung cancer is the most frequent cause of MPE, which results in a bad prognosis. Tumor-derived TNF induces NF-kappaB activation, which is well correlated with pleural effusion volume in a mouse model with injection of lung cancer cells. Suppressing NF-kappaB significant lowered pleural effusion volume (116). At a dose that blocked NF-kappaB activation, bortezomib reduced lung cancer cell-induced MPE accumulation and improved the survival of the animals (117). These studies point to a promoting role of NF-kappaB in MPE and inhibition of NF-kappaB may eliminate MPE.

7. INHIBITING NF-KAPPAB FOR LUNG CANCER CHEMOPREVENTION

Currently there is no validated effective agent for lung cancer prevention (118). Increasing evidences showing that NF-kappaB plays a critical role in lung cancer development suggest NF-kappaB as a target for lung cancer chemoprevention. Interestingly, some agents that have lung cancer preventive potential, including NSAIDs and dietary compounds, possess inhibitory activity on NF-kappaB (119). Oral administration of pomegranate fruit extract, which inhibits NF-kappaB, significantly reduced multiplicity of lung tumor induced by benzo(a)pyrene and N-nitroso-tris-chloroethylurea (120, 121). Feeding mice with zerumbone, a tropical ginger sespuiterpene that can repress NF-kappaB, does-dependently inhibited multiplicity of lung adenoma induced by NNK.

Chemoprevention involves prolonged use of preventive agents. The long-time use of the NF-kappaB inhibitors or anti-inflammatory drugs is likely to result in un-tolerable side-effects (122). Thus, dedicated single NF-kappaB inhibitors are unlikely to be use as chemoprevention agents (119). It has been proposed that logically constructed mixtures of agents or combination treatments are a better choice for lung cancer chemoprevention (123, 124). This strategy would improve the efficacy of cancer prevention while eliminate the possible side effects.

The critical question unanswered is whether NF-kappaB inhibition can reduce human lung cancer incidence in vivo. The drugs used in experiments, as mentioned above, block several pathways. Though these drugs could be good candidates for chemoprevention, it is unclear that how much their NF-kappaB inhibiting activity contributes to the reduced tumor burden in animals and in humans.

8. CONCERNS ABOUT INHIBITING NF-kappaB IN LUNG CANCER THERAPY AND PREVENTION

Along with the rapid development of NF-kappaB inhibitors, general safety and efficacy regarding NF-kappaB inhibition in cancer therapy have been concerned over years. The first concern is that NF-kappaB inhibition may compromise immunity. Due to its pivotal roles in both innate and adaptive immunity, NF-kappaB is important for humans to defend themselves from environmental assaults such as microbe, physical and chemical damages (125). Thus, systemic administration of NF-kappaB inhibitors may impair immune response. Further, NF-kappaB inhibitors may also blunt anticancer immunity (59, 126). It remains to be determined whether NF-kappaB inhibition attenuates or potentiates the efficacy of anti-tumor agents in vivo. Careful clinical evaluation of a NF-kappaB inhibitor in individual cancer patient is crucial. In this regard, the doses of NF-kappaB inhibitors and administrating schedule are critical (59, 122, 127).

The second concern comes from the rather complex and even opposite functions of NF-kappaB in different cells and tissues (46, 122). Although NF-kappaB is shown to promote lung carcinogenesis, it may function as a tumor suppressor in other organs. The contradictory effects may occur at different carcinogenic stages and are likely associated with different carcinogens and different genetic backgrounds of the patients.

The third concern is the potential off-target effect of the NF-kappaB inhibitors. The function of bortezomib is not restricted to NF-kappaB (128), because it inhibits proteosome that would cause accumulation of other proteins that are degraded via proteosome. For example, bortezomib promotes proliferation of prostate cells by stabilizing steroid receptor coactivator-3 (129), raising the concern that bortezomib may increase the risk of prostate cancer. The widely used NF-kappaB inhibition approach with IkappaB SR overexpression also has potential off-target effects that blunt p53 or interfere expression of unrelated genes (18, 130).

9. SUMMARY AND PERSPECTIVE

Although there is no compelling evidence showing that lung cancer cells are addicted to NF-kappaB for survival, NF-kappaB inhibition has been demonstrated to be a promising adjuvant treatment in improving the efficacy of chemotherapy and radiation. Because both the constitutive and therapeutic-induced NF-kappaB activations blunt the cancer cell-killing effects of the therapy, blocking NF-kappaB may potentiate anticancer activity. With piled data showing NF-kappaB is activated in early phase of lung cancer development and growing knowledge on NF-kappaB's functions in tumorigenesis, it is reasonable to hypothesize that NF-kappaB could be a target for lung cancer chemoprevention. However, due to NF-kappaB's pivotal physiological functions in normal cells, particularly in immune cells, sustained and systemic NF-kappaB inhibition may have severe adverse effect. To develop approaches delivering NF-kappaB inhibition more specifically into transformed cells and immune cells residing in tumor-prone microenvironments would be a good direction in solving this problem. Naturally occurring compounds with NF-kappaB suppressing properties are of great interest in relieving inflammation and preventing lung cancer (80). Because TNFalpha is involved in inflammation-associated lung carcinogenesis and blocking NF-kappaB promotes TNFalpha-induced apoptosis in lung cancer cells, NF-kappaB blockage may convert TNFalpha from a tumor promoter to a tumor suppressor (26, 50, 80), making NF-kappaB suppressing compounds potential chemopreventive agents against lung cancer (80). Along with the progress in elucidating NF-kappaB activation mechanisms in tumors, identifying biomarkers for indications for NF-kappaB inhibitor application, and developing malignant cell-specific NF-kappaB inhibition approaches, NF-kappaB inhibition in chemoprevention and chemotherapy against lung cancer would be more clinically relevant in near future.

10. ACKNOWLEDGEMENTS

We apologize that numerous reports were unable to be cited due to the space limit. The research in this laboratory is supported in part by grants from the National Institute of Environmental Health Sciences, NIH (R01ES017328) and Department of Energy Low Dose Radiation Research Program (DE-FG02-09ER64783).

11. REFERENCES

1. A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, T. Murray and M. J. Thun: Cancer statistics, 2008. CA Cancer J Clin, 58(2), 71-96 (2008)
doi:10.3322/CA.2007.0010
PMid:18287387

2. B. N. Ames and L. S. Gold: The causes and prevention of cancer: the role of environment. Biotherapy, 11(2-3), 205-20 (1998)
doi:10.1023/A:1007971204469
PMid:9677052

3. A. Onn, M. Tsuboi and N. Thatcher: Treatment of non-small-cell lung cancer: a perspective on the recent advances and the experience with gefitinib. Br J Cancer, 91 Suppl 2, S11-7 (2004)
doi:10.1038/sj.bjc.6602062
PMid:15340373    PMCid:2750809

4. D. Hanahan and R. A. Weinberg: The hallmarks of cancer. Cell, 100(1), 57-70 (2000)

5. M. S. Hayden and S. Ghosh: Signaling to NF-kappaB. Genes Dev, 18(18), 2195-224 (2004)
doi:10.1101/gad.1228704
PMid:20001209

6. Y. Lin, L. Bai, W. Chen and S. Xu: The NF-kappaB activation pathways, emerging molecular targets for cancer prevention and therapy. Expert Opin Ther Targets, 14(1), 45-55 (2010)
doi:10.1517/14728220903431069

7. A. Devin, A. Cook, Y. Lin, Y. Rodriguez, M. Kelliher and Z. Liu: The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation. Immunity, 12(4), 419-29 (2000)
doi:10.1016/S1074-7613(00)80194-6
PMid:11429546

8. J. Yang, Y. Lin, Z. Guo, J. Cheng, J. Huang, L. Deng, W. Liao, Z. Chen, Z. Liu and B. Su: The essential role of MEKK3 in TNF-induced NF-kappaB activation. Nat Immunol, 2(7), 620-4 (2001)
doi:10.1038/89769
PMid:16056267    PMCid:1551980

9. Z. J. Chen: Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol, 7(8), 758-65 (2005)
doi:10.1038/ncb0805-758
PMid:20048074

10. H. C. Thoms, C. J. Loveridge, J. Simpson, A. Clipson, K. Reinhardt, M. G. Dunlop and L. A. Stark: Nucleolar targeting of RelA(p65) is regulated by COMMD1-dependent ubiquitination. Cancer Res, 70(1), 139-49 (2010)
doi:10.1158/0008-5472.CAN-09-1397
PMid:17301840

11. N. Festjens, T. Vanden Berghe, S. Cornelis and P. Vandenabeele: RIP1, a kinase on the crossroads of a cell's decision to live or die. Cell Death Differ, 14(3), 400-10 (2007)
doi:10.1038/sj.cdd.4402085
PMid:16547522

12. C. J. Wu, D. B. Conze, T. Li, S. M. Srinivasula and J. D. Ashwell: NEMO is a sensor of Lys 63-linked polyubiquitination and functions in NF-kappaB activation. Nat Cell Biol, 8(4), 398-406 (2006)
doi:10.1038/ncb1384
PMid:20188669

13. F. Renner, R. Moreno and M. L. Schmitz: SUMOylation-Dependent Localization of IKKvarepsilon in PML Nuclear Bodies Is Essential for Protection against DNA-Damage-Triggered Cell Death. Mol Cell, 37(4), 503-515 (2010)
doi:10.1016/j.molcel.2010.01.018
PMid:18997794    PMCid:2676931

14. B. J. Zarnegar, Y. Wang, D. J. Mahoney, P. W. Dempsey, H. H. Cheung, J. He, T. Shiba, X. Yang, W. C. Yeh, T. W. Mak, R. G. Korneluk and G. Cheng: Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol, 9(12), 1371-8 (2008)
doi:10.1038/ni.1676
PMid:19847166    PMCid:2783335

15. D. A. Barbie, P. Tamayo, J. S. Boehm, S. Y. Kim, S. E. Moody, I. F. Dunn, A. C. Schinzel, P. Sandy, E. Meylan, C. Scholl, S. Frohling, E. M. Chan, M. L. Sos, K. Michel, C. Mermel, S. J. Silver, B. A. Weir, J. H. Reiling, Q. Sheng, P. B. Gupta, R. C. Wadlow, H. Le, S. Hoersch, B. S. Wittner, S. Ramaswamy, D. M. Livingston, D. M. Sabatini, M. Meyerson, R. K. Thomas, E. S. Lander, J. P. Mesirov, D. E. Root, D. G. Gilliland, T. Jacks and W. C. Hahn: Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature, 462(7269), 108-12 (2009)
doi:10.1038/nature08460

16. T. Kato, Jr., M. Delhase, A. Hoffmann and M. Karin: CK2 Is a C-Terminal IkappaB Kinase Responsible for NF-kappaB Activation during the UV Response. Mol Cell, 12(4), 829-39 (2003)
doi:10.1016/S1097-2765(03)00358-7
PMid:15653325

17. P. Viatour, M. P. Merville, V. Bours and A. Chariot: Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. Trends Biochem Sci, 30(1), 43-52 (2005)
doi:10.1016/j.tibs.2004.11.009
PMid:18636537    PMCid:2688738

18. W. Chen, X. Wang, L. Bai, X. Liang, J. Zhuang and Y. Lin: Blockage of NF-kappaB by IKKbeta- or RelA-siRNA rather than the NF-kappaB super-suppressor IkappaBalpha mutant potentiates adriamycin-induced cytotoxicity in lung cancer cells. J Cell Biochem, 105(2), 554-61 (2008)
doi:10.1002/jcb.21856

19. G. M. Hur, J. Lewis, Q. Yang, Y. Lin, H. Nakano, S. Nedospasov and Z. G. Liu: The death domain kinase RIP has an essential role in DNA damage-induced NF-kappa B activation. Genes Dev, 17(7), 873-82 (2003)
doi:10.1101/gad.1062403

20. K. J. Campbell, S. Rocha and N. D. Perkins: Active repression of antiapoptotic gene expression by RelA(p65) NF-kappa B. Mol Cell, 13(6), 853-65 (2004)
doi:10.1016/S1097-2765(04)00131-5
PMid:15775976    PMCid:556410

21. S. Rocha, M. D. Garrett, K. J. Campbell, K. Schumm and N. D. Perkins: Regulation of NF-kappaB and p53 through activation of ATR and Chk1 by the ARF tumour suppressor. EMBO J, 24(6), 1157-69 (2005)
doi:10.1038/sj.emboj.7600608
PMid:11150309

22. F. Chen, Y. Lu, Z. Zhang, V. Vallyathan, M. Ding, V. Castranova and X. Shi: Opposite effect of NF-kappa B and c-Jun N-terminal kinase on p53-independent GADD45 induction by arsenite. J Biol Chem, 276(14), 11414-9 (2001)
doi:10.1074/jbc.M011682200
PMid:18301380

23. M. Karin: The IkappaB kinase - a bridge between inflammation and cancer. Cell Res, 18(3), 334-42 (2008)
doi:10.1038/cr.2008.30
PMid:11875461

24. M. Karin and A. Lin: NF-kappaB at the crossroads of life and death. Nat Immunol, 3(3), 221-7 (2002)
doi:10.1038/ni0302-221
PMid:17296806

25. F. R. Greten, L. Eckmann, T. F. Greten, J. M. Park, Z. W. Li, L. J. Egan, M. F. Kagnoff and M. Karin: IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell, 118(3), 285-96 (2004)
PMid:11713531

26. W. Ju, X. Wang, H. Shi, W. Chen, S. A. Belinsky and Y. Lin: A critical role of luteolin-induced reactive oxygen species in blockage of tumor necrosis factor-activated nuclear factor-kappaB pathway and sensitization of apoptosis in lung cancer cells. Mol Pharmacol, 71(5), 1381-8 (2007)
doi:10.1124/mol.106.032185

27. G. Tang, Y. Minemoto, B. Dibling, N. H. Purcell, Z. Li, M. Karin and A. Lin: Inhibition of JNK activation through NF-kappaB target genes. Nature, 414(6861), 313-7 (2001)
doi:10.1038/35104568
PMid:15558024

28. B. Kaltschmidt, C. Kaltschmidt, T. G. Hofmann, S. P. Hehner, W. Droge and M. L. Schmitz: The pro- or anti-apoptotic function of NF-kappaB is determined by the nature of the apoptotic stimulus. Eur J Biochem, 267(12), 3828-35 (2000)
doi:10.1046/j.1432-1327.2000.01421.x
PMid:20009901

29. K. M. Kim and Y. J. Lee: Amiloride augments TRAIL-induced apoptotic death by inhibiting phosphorylation of kinases and phosphatases associated with the P13K-Akt pathway. Oncogene, 24(3), 355-66 (2005)
doi:10.1038/sj.onc.1208213
PMid:16175180

30. J. Li, H. Jia, L. Xie, X. Wang, H. He, Y. Lin and L. Hu: Association of constitutive nuclear factor-kappaB activation with aggressive aspects and poor prognosis in cervical cancer. Int J Gynecol Cancer, 19(8), 1421-6 (2009)
PMid:18215193

31. M. Karin and F. R. Greten: NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol, 5(10), 749-59 (2005)
doi:10.1038/nri1703
PMid:16424045

32. X. Jin, Z. Wang, L. Qiu, D. Zhang, Z. Guo, Z. Gao, C. Deng, F. Wang, S. Wang and C. Guo: Potential biomarkers involving IKK/RelA signal in early stage non-small cell lung cancer. Cancer Sci, 99(3), 582-9 (2008)
doi:10.1111/j.1349-7006.2007.00713.x
PMid:17316570

33. X. Wang, W. Ju, J. Renouard, J. Aden, S. A. Belinsky and Y. Lin: 17-allylamino-17-demethoxygeldanamycin synergistically potentiates tumor necrosis factor-induced lung cancer cell death by blocking the nuclear factor-kappaB pathway. Cancer Res, 66(2), 1089-95 (2006)
doi:10.1158/0008-5472.CAN-05-2698
PMid:20129250

34. X. Wang, W. Chen and Y. Lin: Sensitization of TNF-induced cytotoxicity in lung cancer cells by concurrent suppression of the NF-kappaB and Akt pathways. Biochem Biophys Res Commun, 355(3), 807-12 (2007)
doi:10.1016/j.bbrc.2007.02.030
PMid:20406971

35. H. Takahashi, H. Ogata, R. Nishigaki, D. H. Broide and M. Karin: Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation. Cancer Cell, 17(1), 89-97 (2010)
doi:10.1016/j.ccr.2009.12.008
PMid:19847165    PMCid:2780341

36. D. S. Basseres, A. Ebbs, E. Levantini and A. S. Baldwin: Requirement of the NF-kappaB subunit p65/RelA for K-Ras-induced lung tumorigenesis. Cancer Res, 70(9), 3537-46 (2010)
doi:10.1158/0008-5472.CAN-09-4290
PMid:16864557

37. E. Meylan, A. L. Dooley, D. M. Feldser, L. Shen, E. Turk, C. Ouyang and T. Jacks: Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma. Nature, 462(7269), 104-7 (2009)
doi:10.1038/nature08462

38. C. J. Smith, T. A. Perfetti and J. A. King: Perspectives on pulmonary inflammation and lung cancer risk in cigarette smokers. Inhal Toxicol, 18(9), 667-77 (2006)
doi:10.1080/08958370600742821
PMid:20354166

39. A. Emmendoerffer, M. Hecht, T. Boeker, M. Mueller and U. Heinrich: Role of inflammation in chemical-induced lung cancer. Toxicol Lett, 112-113, 185-91 (2000)
doi:10.1016/S0378-4274(99)00285-4
PMid:15790591

40. K. K. Wong, T. Jacks and G. Dranoff: NF-kappaB fans the flames of lung carcinogenesis. Cancer Prev Res (Phila Pa), 3(4), 403-5 (2010)
doi:10.1158/1940-6207.CAPR-10-0042
PMid:16410802

41. J. Tsurutani, S. S. Castillo, J. Brognard, C. A. Granville, C. Zhang, J. J. Gills, J. Sayyah and P. A. Dennis: Tobacco components stimulate Akt-dependent proliferation and NFkappaB-dependent survival in lung cancer cells. Carcinogenesis, 26(7), 1182-95 (2005)
doi:10.1093/carcin/bgi072
PMid:14585846

42. S. Janssens and J. Tschopp: Signals from within: the DNA-damage-induced NF-kappaB response. Cell Death Differ, 13(5), 773-84 (2006)
doi:10.1038/sj.cdd.4401843
PMid:16109772    PMCid:1194899

43. J. A. Gustin, O. N. Ozes, H. Akca, R. Pincheira, L. D. Mayo, Q. Li, J. R. Guzman, C. K. Korgaonkar and D. B. Donner: Cell type-specific expression of the IkappaB kinases determines the significance of phosphatidylinositol 3-kinase/Akt signaling to NF-kappa B activation. J Biol Chem, 279(3), 1615-20 (2004)
doi:10.1074/jbc.M306976200
PMid:17533369

44. G. Chen, M. S. Bhojani, A. C. Heaford, D. C. Chang, B. Laxman, D. G. Thomas, L. B. Griffin, J. Yu, J. M. Coppola, T. J. Giordano, L. Lin, D. Adams, M. B. Orringer, B. D. Ross, D. G. Beer and A. Rehemtulla: Phosphorylated FADD induces NF-{kappa}B, perturbs cell cycle, and is associated with poor outcome in lung adenocarcinomas. Proc Natl Acad Sci U S A, 102(35), 12507-12 (2005)
doi:10.1073/pnas.0500397102
PMid:15102437

45. G. Sethi, K. S. Ahn, M. M. Chaturvedi and B. B. Aggarwal: Epidermal growth factor (EGF) activates nuclear factor-kappaB through IkappaBalpha kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IkappaBalpha. Oncogene, 26(52), 7324-32 (2007)
doi:10.1038/sj.onc.1210544
PMid:16530406

46.N. D. Perkins: NF-kappaB: tumor promoter or suppressor? Trends Cell Biol, 14(2), 64-9 (2004)
doi:10.1016/j.tcb.2003.12.004
PMid:18000061    PMCid:2141808

47. E. Pikarsky and Y. Ben-Neriah: NF-kappaB inhibition: a double-edged sword in cancer? Eur J Cancer, 42(6), 779-84 (2006)
doi:10.1016/j.ejca.2006.01.011
PMid:20354164

48. G. T. Stathopoulos, T. P. Sherrill, D. S. Cheng, R. M. Scoggins, W. Han, V. V. Polosukhin, L. Connelly, F. E. Yull, B. Fingleton and T. S. Blackwell: Epithelial NF-kappaB activation promotes urethane-induced lung carcinogenesis. Proc Natl Acad Sci U S A, 104(47), 18514-9 (2007)
doi:10.1073/pnas.0705316104
PMid:18954521    PMCid:2631033

49. J. Deng, J. Fujimoto, X. F. Ye, T. Y. Men, C. S. Van Pelt, Y. L. Chen, X. F. Lin, H. Kadara, Q. Tao, D. Lotan and R. Lotan: Knockout of the tumor suppressor gene Gprc5a in mice leads to NF-kappaB activation in airway epithelium and promotes lung inflammation and tumorigenesis. Cancer Prev Res (Phila Pa), 3(4), 424-37 (2010)
doi:10.1158/1940-6207.CAPR-10-0032
PMid:10647931

50. X. Wang and Y. Lin: Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacol Sin, 29(11), 1275-88 (2008)
doi:10.1111/j.1745-7254.2008.00889.x
PMid:15294155

51. S. I. Grivennikov, F. R. Greten and M. Karin: Immunity, inflammation, and cancer. Cell, 140(6), 883-99 (2010)
PMid:18849299

52. C. Y. Chu, S. T. Cha, W. C. Lin, P. H. Lu, C. T. Tan, C. C. Chang, B. R. Lin, S. H. Jee and M. L. Kuo: Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12)-enhanced angiogenesis of human basal cell carcinoma cells involves ERK1/2-NF-kappaB/interleukin-6 pathway. Carcinogenesis, 30(2), 205-13 (2009)
doi:10.1093/carcin/bgn228
PMid:18390755

53. S. K. Raghuwanshi, M. W. Nasser, X. Chen, R. M. Strieter and R. M. Richardson: Depletion of beta-arrestin-2 promotes tumor growth and angiogenesis in a murine model of lung cancer. J Immunol, 180(8), 5699-706 (2008)
PMid:17276388

54. S. P. Tabruyn and A. W. Griffioen: Molecular pathways of angiogenesis inhibition. Biochem Biophys Res Commun, 355(1), 1-5 (2007)
doi:10.1016/j.bbrc.2007.01.123
PMid:15539952

55. M. A. Huber, H. Beug and T. Wirth: Epithelial-mesenchymal transition: NF-kappaB takes center stage. Cell Cycle, 3(12), 1477-80 (2004)
PMid:19073147

56. C. Y. Huang, Y. C. Fong, C. Y. Lee, M. Y. Chen, H. C. Tsai, H. C. Hsu and C. H. Tang: CCL5 increases lung cancer migration via PI3K, Akt and NF-kappaB pathways. Biochem Pharmacol, 77(5), 794-803 (2009)
doi:10.1016/j.bcp.2008.11.014
PMid:17916907

57. C. H. Tang, T. W. Tan, W. M. Fu and R. S. Yang: Involvement of matrix metalloproteinase-9 in stromal cell-derived factor-1/CXCR4 pathway of lung cancer metastasis. Carcinogenesis, 29(1), 35-43 (2008)
doi:10.1093/carcin/bgm220
PMid:20101151

58. J. Goffin, C. Lacchetti, P. M. Ellis, Y. C. Ung and W. K. Evans: First-line systemic chemotherapy in the treatment of advanced non-small cell lung cancer: a systematic review. J Thorac Oncol, 5(2), 260-74 (2010) doi:10.1097/JTO.0b013e3181c6f03501243894-201002000-00021 (pii)
doi:10.1097/JTO.0b013e3181c6f035
PMid:15803156

59. C. Nakanishi and M. Toi: Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat Rev Cancer, 5(4), 297-309 (2005)
doi:10.1038/nrc1588
PMid:11828291

60. D. R. Jones, R. M. Broad, L. D. Comeau, S. J. Parsons and M. W. Mayo: Inhibition of nuclear factor kappaB chemosensitizes non-small cell lung cancer through cytochrome c release and caspase activation. J Thorac Cardiovasc Surg, 123(2), 310-7 (2002)
doi:10.1067/mtc.2002.118684
PMid:15366685

61. C. E. Denlinger, B. K. Rundall and D. R. Jones: Modulation of antiapoptotic cell signaling pathways in non-small cell lung cancer: the role of NF-kappaB. Semin Thorac Cardiovasc Surg, 16(1), 28-39 (2004)
doi:10.1053/j.semtcvs.2003.12.004
PMid:19212815

62. H. M. Shen and V. Tergaonkar: NFkappaB signaling in carcinogenesis and as a potential molecular target for cancer therapy. Apoptosis, 14(4), 348-63 (2009)
doi:10.1007/s10495-009-0315-0
PMid:14708018

63. M. Karin, Y. Yamamoto and Q. M. Wang: The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov, 3(1), 17-26 (2004)
doi:10.1038/nrd1279
PMid:11410792

64. H. Oyaizu, Y. Adachi, T. Okumura, M. Okigaki, N. Oyaizu, S. Taketani, K. Ikebukuro, S. Fukuhara and S. Ikehara: Proteasome inhibitor 1 enhances paclitaxel-induced apoptosis in human lung adenocarcinoma cell line. Oncol Rep, 8(4), 825-9 (2001)
PMid:17620439

65. J. Voortman, T. P. Resende, M. A. Abou El Hassan, G. Giaccone and F. A. Kruyt: TRAIL therapy in non-small cell lung cancer cells: sensitization to death receptor-mediated apoptosis by proteasome inhibitor bortezomib. Mol Cancer Ther, 6(7), 2103-12 (2007)
doi:10.1158/1535-7163.MCT-07-0167
PMid:17671158

66. A. M. Davies, P. N. Lara, Jr., P. C. Mack and D. R. Gandara: Incorporating bortezomib into the treatment of lung cancer. Clin Cancer Res, 13(15 Pt 2), s4647-51 (2007)
doi:10.1158/1078-0432.CCR-07-0334
PMid:19633475

67. T. J. Lynch, D. Fenton, V. Hirsh, D. Bodkin, E. L. Middleman, A. Chiappori, B. Halmos, R. Favis, H. Liu, W. L. Trepicchio, O. Eton and F. A. Shepherd: A randomized phase 2 study of erlotinib alone and in combination with bortezomib in previously treated advanced non-small cell lung cancer. J Thorac Oncol, 4(8), 1002-9 (2009)
doi:10.1097/JTO.0b013e3181aba89f
PMid:19362945

68. G. V. Scagliotti, P. Ceppi, E. Capelletto and S. Novello: Updated clinical information on multitargeted antifolates in lung cancer. Clin Lung Cancer, 10 Suppl 1, S35-40 (2009)
doi:10.3816/CLC.2009.s.006
PMid:19401697    PMCid:2694419

69. A. Z. Dudek, K. Lesniewski-Kmak, N. J. Shehadeh, O. N. Pandey, M. Franklin, R. A. Kratzke, E. W. Greeno and P. Kumar: Phase I study of bortezomib and cetuximab in patients with solid tumours expressing epidermal growth factor receptor. Br J Cancer, 100(9), 1379-84 (2009)
doi:10.1038/sj.bjc.6605043
PMid:9817203

70. M. J. Yin, Y. Yamamoto and R. B. Gaynor: The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature, 396(6706), 77-80 (1998)
doi:10.1038/23948
PMid:11839649

71. K. S. Berman, U. N. Verma, G. Harburg, J. D. Minna, M. H. Cobb and R. B. Gaynor: Sulindac enhances tumor necrosis factor-alpha-mediated apoptosis of lung cancer cell lines by inhibition of nuclear factor-kappaB. Clin Cancer Res, 8(2), 354-60 (2002)
PMid:15256475

72. S. Shishodia and B. B. Aggarwal: Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates activation of cigarette smoke-induced nuclear factor (NF)-kappaB by suppressing activation of IkappaBalpha kinase in human non-small cell lung carcinoma: correlation with suppression of cyclin D1, COX-2, and matrix metalloproteinase-9. Cancer Res, 64(14), 5004-12 (2004)
doi:10.1158/0008-5472.CAN-04-0206
PMid:11054378

73. C. K. Weber, S. Liptay, T. Wirth, G. Adler and R. M. Schmid: Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. Gastroenterology, 119(5), 1209-18 (2000)
doi:10.1053/gast.2000.19458
PMid:17440102

74. J. D. Lay, C. C. Hong, J. S. Huang, Y. Y. Yang, C. Y. Pao, C. H. Liu, Y. P. Lai, G. M. Lai, A. L. Cheng, I. J. Su and S. E. Chuang: Sulfasalazine suppresses drug resistance and invasiveness of lung adenocarcinoma cells expressing AXL. Cancer Res, 67(8), 3878-87 (2007)
doi:10.1158/0008-5472.CAN-06-3191
PMid:17145842

75. Y. C. Lin, C. T. Shun, M. S. Wu and C. C. Chen: A novel anticancer effect of thalidomide: inhibition of intercellular adhesion molecule-1-mediated cell invasion and metastasis through suppression of nuclear factor-kappaB. Clin Cancer Res, 12(23), 7165-73 (2006)
doi:10.1158/1078-0432.CCR-06-1393

76. A. Matsumori, Y. Nunokawa and S. Sasayama: Nifedipine inhibits activation of transcription factor NF-kappaB. Life Sci, 67(21), 2655-61 (2000)
doi:10.1016/S0024-3205(00)00849-3
PMid:17954363

77. X. Gao, M. Iwai, S. Inaba, Y. Tomono, H. Kanno, M. Mogi and M. Horiuchi: Attenuation of monocyte chemoattractant protein-1 expression via inhibition of nuclear factor-kappaB activity in inflammatory vascular injury. Am J Hypertens, 20(11), 1170-5 (2007)
PMid:18204791

78. N. Tomita, K. Yamasaki, K. Izawa, Y. Kunugiza, M. K. Osako, T. Ogihara and R. Morishita: Inhibition of experimental abdominal aortic aneurysm progression by nifedipine. Int J Mol Med, 21(2), 239-44 (2008)
PMid:16889756

79. B. B. Aggarwal, S. Shishodia, S. K. Sandur, M. K. Pandey and G. Sethi: Inflammation and cancer: how hot is the link? Biochem Pharmacol, 72(11), 1605-21 (2006)
doi:10.1016/j.bcp.2006.06.029
PMid:18991571    PMCid:2615542

80. Y. Lin, R. Shi, X. Wang and H. M. Shen: Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets, 8(7), 634-46 (2008)
doi:10.2174/156800908786241050

81. D. F. Birt, S. Hendrich and W. Wang: Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther, 90(2-3), 157-77 (2001)
doi:10.1016/S0163-7258(01)00137-1
PMid:15884858

82. S. Y. Wang, R. Feng, Y. Lu, L. Bowman and M. Ding: Inhibitory effect on activator protein-1, nuclear factor-kappaB, and cell transformation by extracts of strawberries (Fragaria x ananassa Duch.). J Agric Food Chem, 53(10), 4187-93 (2005)
doi:10.1021/jf0478049
PMid:18044836

83. Y. W. Shih, P. S. Chen, C. H. Wu, Y. F. Jeng and C. J. Wang: Alpha-chaconine-reduced metastasis involves a PI3K/Akt signaling pathway with downregulation of NF-kappaB in human lung adenocarcinoma A549 cells. J Agric Food Chem, 55(26), 11035-43 (2007)
doi:10.1021/jf072423r
PMid:12526088

84. K. Y. Lee, J. S. Park, Y. K. Jee and G. D. Rosen: Triptolide sensitizes lung cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by inhibition of NF-kappaB activation. Exp Mol Med, 34(6), 462-8 (2002)
PMid:17516865

85. S. K. Sandur, K. S. Ahn, H. Ichikawa, G. Sethi, S. Shishodia, R. A. Newman and B. B. Aggarwal: Zyflamend, a polyherbal preparation, inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of NF-kappa B activation and NF-kappa B-regulated gene products. Nutr Cancer, 57(1), 78-87 (2007)
PMid:16820889

86. T. Ikezoe, Y. Yang, T. Saitoh, D. Heber, R. McKenna, H. Taguchi and H. P. Koeffler: PC-SPES down-regulates COX-2 via inhibition of NF-kappaB and C/EBPbeta in non-small cell lung cancer cells. Int J Oncol, 29(2), 453-61 (2006)

87. J. H. Woo, D. Li, K. Wilsbach, H. Orita, J. Coulter, E. Tully, T. K. Kwon, S. Xu and E. Gabrielson: Coix seed extract, a commonly used treatment for cancer in China, inhibits NFkappaB and protein kinase C signaling. Cancer Biol Ther, 6(12), 2005-11 (2007)
doi:10.4161/cbt.6.12.5168
PMid:15350828

88. Y. L. Hsu, P. L. Kuo and C. C. Lin: Proliferative inhibition, cell-cycle dysregulation, and induction of apoptosis by ursolic acid in human non-small cell lung cancer A549 cells. Life Sci, 75(19), 2303-16 (2004)
doi:10.1016/j.lfs.2004.04.027
PMid:17028156

89. K. S. Ahn, G. Sethi and B. B. Aggarwal: Embelin, an inhibitor of X chromosome-linked inhibitor-of-apoptosis protein, blocks nuclear factor-kappaB (NF-kappaB) signaling pathway leading to suppression of NF-kappaB-regulated antiapoptotic and metastatic gene products. Mol Pharmacol, 71(1), 209-19 (2007)
doi:10.1124/mol.106.028787

90. A. A. Shaik, D. L. Hermanson and C. Xing: Identification of methysticin as a potent and non-toxic NF-kappaB inhibitor from kava, potentially responsible for kava's chemopreventive activity. Bioorg Med Chem Lett, 19(19), 5732-6 (2009)
doi:10.1016/j.bmcl.2009.08.003
PMid:19284764    PMCid:2670969

91. J. C. Lin, S. C. Yang, T. M. Hong, S. L. Yu, Q. Shi, L. Wei, H. Y. Chen, P. C. Yang and K. H. Lee: Phenanthrene-based tylophorine-1 (PBT-1) inhibits lung cancer cell growth through the Akt and NF-kappaB pathways. J Med Chem, 52(7), 1903-11 (2009)
doi:10.1021/jm801344j
PMid:11359792

92. C. Ji, K. R. Kozak and L. J. Marnett: IkappaB kinase, a molecular target for inhibition by 4-hydroxy-2-nonenal. J Biol Chem, 276(21), 18223-8 (2001)
doi:10.1074/jbc.M101266200
PMid:16230421

93. S. Shishodia, A. M. Gutierrez, R. Lotan and B. B. Aggarwal: N-(4-hydroxyphenyl)retinamide inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of I(kappa)B(alpha) kinase and nuclear factor-kappaB-regulated gene products. Cancer Res, 65(20), 9555-65 (2005)
doi:10.1158/0008-5472.CAN-05-1585
PMid:16707469

94. G. Imre, V. Gekeler, A. Leja, T. Beckers and M. Boehm: Histone deacetylase inhibitors suppress the inducibility of nuclear factor-kappaB by tumor necrosis factor-alpha receptor-1 down-regulation. Cancer Res, 66(10), 5409-18 (2006)
doi:10.1158/0008-5472.CAN-05-4225
PMid:17560552

95. J. Mi, X. Zhang, Y. Liu, S. K. Reddy, Z. N. Rabbani, B. A. Sullenger and B. M. Clary: NF-kappaB inhibition by an adenovirus expressed aptamer sensitizes TNFalpha-induced apoptosis. Biochem Biophys Res Commun, 359(3), 475-80 (2007)
doi:10.1016/j.bbrc.2007.05.125

96. V. Tergaonkar, M. Pando, O. Vafa, G. Wahl and I. Verma: p53 stabilization is decreased upon NFkappaB activation: a role for NFkappaB in acquisition of resistance to chemotherapy. Cancer Cell, 1(5), 493-503 (2002)
doi:10.1016/S1535-6108(02)00068-5
PMid:17786042

97. A. Dey, E. T. Wong, P. Bist, V. Tergaonkar and D. P. Lane: Nutlin-3 inhibits the NFkappaB pathway in a p53-dependent manner: implications in lung cancer therapy. Cell Cycle, 6(17), 2178-85 (2007)
doi:10.4161/cc.6.17.4643
PMid:15630414

98. T. Marumoto, D. Zhang and H. Saya: Aurora-A - a guardian of poles. Nat Rev Cancer, 5(1), 42-50 (2005)
doi:10.1038/nrc1526
PMid:17145803

99. R. D. Carvajal, A. Tse and G. K. Schwartz: Aurora kinases: new targets for cancer therapy. Clin Cancer Res, 12(23), 6869-75 (2006)
doi:10.1158/1078-0432.CCR-06-1405
PMid:17308110

100. P. Briassouli, F. Chan, K. Savage, J. S. Reis-Filho and S. Linardopoulos: Aurora-A regulation of nuclear factor-kappaB signaling by phosphorylation of IkappaBalpha. Cancer Res, 67(4), 1689-95 (2007)
doi:10.1158/0008-5472.CAN-06-2272
PMid:20303878

101. Q. Cheng, H. H. Lee, Y. Li, T. P. Parks and G. Cheng: Upregulation of Bcl-x and Bfl-1 as a potential mechanism of chemoresistance, which can be overcome by NF-kappaB inhibition. Oncogene, 19(42), 4936-40 (2000)
doi:10.1038/sj.onc.1203861
PMid:11039911

102. Y. Li, F. Ahmed, S. Ali, P. A. Philip, O. Kucuk and F. H. Sarkar: Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells. Cancer Res, 65(15), 6934-42 (2005)
doi:10.1158/0008-5472.CAN-04-4604
PMid:16061678

103. D. R. Jones, R. M. Broad, L. V. Madrid, A. S. Baldwin, Jr. and M. W. Mayo: Inhibition of NF-kappaB sensitizes non-small cell lung cancer cells to chemotherapy-induced apoptosis. Ann Thorac Surg, 70(3), 930-6; discussion 936-7 (2000)
doi:10.1016/S0003-4975(00)01635-0

104. S. Osaki, Y. Nakanishi, K. Takayama, X. H. Pei, H. Ueno and N. Hara: Transfer of IkappaBalpha gene increase the sensitivity of paclitaxel mediated with caspase 3 activation in human lung cancer cell. J Exp Clin Cancer Res, 22(1), 69-75 (2003)
PMid:12725325

105. S. Sen, H. Sharma and N. Singh: Curcumin enhances Vinorelbine mediated apoptosis in NSCLC cells by the mitochondrial pathway. Biochem Biophys Res Commun, 331(4), 1245-52 (2005)
doi:10.1016/j.bbrc.2005.04.044
PMid:15883009

106. Q. G. Dong, G. M. Sclabas, S. Fujioka, C. Schmidt, B. Peng, T. Wu, M. S. Tsao, D. B. Evans, J. L. Abbruzzese, T. J. McDonnell and P. J. Chiao: The function of multiple IkappaB : NF-kappaB complexes in the resistance of cancer cells to Taxol-induced apoptosis. Oncogene, 21(42), 6510-9 (2002)
doi:10.1038/sj.onc.1205848
PMid:12226754

107. K. R. Grimes, G. W. Warren, F. Fang, Y. Xu and W. H. St Clair: Cyclooxygenase-2 inhibitor, nimesulide, improves radiation treatment against non-small cell lung cancer both in vitro and in vivo. Oncol Rep, 16(4), 771-6 (2006)
PMid:16969492

108. K. R. Grimes, C. Daosukho, Y. Zhao, A. Meigooni and W. St Clair: Proteasome inhibition improves fractionated radiation treatment against non-small cell lung cancer: an antioxidant connection. Int J Oncol, 27(4), 1047-52 (2005)
PMid:16142322

109. H. F. Liao, C. D. Kuo, Y. C. Yang, C. P. Lin, H. C. Tai, Y. Y. Chen and Y. J. Chen: Resveratrol enhances radiosensitivity of human non-small cell lung cancer NCI-H838 cells accompanied by inhibition of nuclear factor-kappa B activation. J Radiat Res (Tokyo), 46(4), 387-93 (2005)
doi:10.1269/jrr.46.387
PMid:16394628

110. M. Zheng, S. E. Morgan-Lappe, J. Yang, K. M. Bockbrader, D. Pamarthy, D. Thomas, S. W. Fesik and Y. Sun: Growth inhibition and radiosensitization of glioblastoma and lung cancer cells by small interfering RNA silencing of tumor necrosis factor receptor-associated factor 2. Cancer Res, 68(18), 7570-8 (2008)
doi:10.1158/0008-5472.CAN-08-0632
PMid:18794145    PMCid:2597026

111. V. B. Andela, E. M. Schwarz, J. E. Puzas, R. J. O'Keefe and R. N. Rosier: Tumor metastasis and the reciprocal regulation of prometastatic and antimetastatic factors by nuclear factor kappaB. Cancer Res, 60(23), 6557-62 (2000)
PMid:11118032

112. T. N. Hartmann, J. A. Burger, A. Glodek, N. Fujii and M. Burger: CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells. Oncogene, 24(27), 4462-71 (2005)
doi:10.1038/sj.onc.1208621
PMid:15806155

113. J. Ding, J. Li, C. Xue, K. Wu, W. Ouyang, D. Zhang, Y. Yan and C. Huang: Cyclooxygenase-2 induction by arsenite is through a nuclear factor of activated T-cell-dependent pathway and plays an antiapoptotic role in Beas-2B cells. J Biol Chem, 281(34), 24405-13 (2006)
doi:10.1074/jbc.M600751200
PMid:16809336

114. J. Yang, D. Wei and J. Liu: Repressions of MMP-9 expression and NF-kappa B localization are involved in inhibition of lung carcinoma 95-D cell invasion by (-)-epigallocatechin-3-gallate. Biomed Pharmacother, 59(3), 98-103 (2005)
doi:10.1016/j.biopha.2005.01.004

115. L. H. Wei, K. P. Lai, C. A. Chen, C. H. Cheng, Y. J. Huang, C. H. Chou, M. L. Kuo and C. Y. Hsieh: Arsenic trioxide prevents radiation-enhanced tumor invasiveness and inhibits matrix metalloproteinase-9 through downregulation of nuclear factor kappaB. Oncogene, 24(3), 390-8 (2005)
doi:10.1038/sj.onc.1208192
PMid:15531921

116. G. T. Stathopoulos, Z. Zhu, M. B. Everhart, I. Kalomenidis, W. E. Lawson, S. Bilaceroglu, T. E. Peterson, D. Mitchell, F. E. Yull, R. W. Light and T. S. Blackwell: Nuclear factor-kappaB affects tumor progression in a mouse model of malignant pleural effusion. Am J Respir Cell Mol Biol, 34(2), 142-50 (2006)
doi:10.1165/rcmb.2005-0130OC
PMid:16210694    PMCid:2644178

117. I. Psallidas, S. P. Karabela, C. Moschos, T. P. Sherrill, A. Kollintza, S. Magkouta, P. Theodoropoulou, C. Roussos, T. S. Blackwell, I. Kalomenidis and G. T. Stathopoulos: Specific effects of bortezomib against experimental malignant pleural effusion: a preclinical study. Mol Cancer, 9, 56 (2010)
doi:10.1186/1476-4598-9-56
PMid:20219102    PMCid:2841124

118. R. L. Keith: Chemoprevention of lung cancer. Proc Am Thorac Soc, 6(2), 187-93 (2009)
doi:10.1513/pats.200807-067LC
PMid:19349487    PMCid:2674227

119. J. Cuzick, F. Otto, J. A. Baron, P. H. Brown, J. Burn, P. Greenwald, J. Jankowski, C. La Vecchia, F. Meyskens, H. J. Senn and M. Thun: Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol, 10(5), 501-7 (2009)
doi:10.1016/S1470-2045(09)70035-X

120. N. Khan, F. Afaq, M. H. Kweon, K. Kim and H. Mukhtar: Oral consumption of pomegranate fruit extract inhibits growth and progression of primary lung tumors in mice. Cancer Res, 67(7), 3475-82 (2007)
doi:10.1158/0008-5472.CAN-06-3941
PMid:17389758

121. N. Khan, N. Hadi, F. Afaq, D. N. Syed, M. H. Kweon and H. Mukhtar: Pomegranate fruit extract inhibits prosurvival pathways in human A549 lung carcinoma cells and tumor growth in athymic nude mice. Carcinogenesis, 28(1), 163-73 (2007)
doi:10.1093/carcin/bgl145
PMid:16920736

122. M. Karin: Nuclear factor-kappaB in cancer development and progression. Nature, 441(7092), 431-6 (2006)
doi:10.1038/nature04870
PMid:16724054

123. S. S. Hecht, F. Kassie and D. K. Hatsukami: Chemoprevention of lung carcinogenesis in addicted smokers and ex-smokers. Nat Rev Cancer, 9(7), 476-88 (2009)
doi:10.1038/nrc2674
PMid:19550424

124. G. L. Russo: Ins and outs of dietary phytochemicals in cancer chemoprevention. Biochem Pharmacol, 74(4), 533-44 (2007)
doi:10.1016/j.bcp.2007.02.014
PMid:17382300

125. S. Vallabhapurapu and M. Karin: Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol, 27, 693-733 (2009)
doi:10.1146/annurev.immunol.021908.132641
PMid:19302050

126. L. Zitvogel, L. Apetoh, F. Ghiringhelli and G. Kroemer: Immunological aspects of cancer chemotherapy. Nat Rev Immunol, 8(1), 59-73 (2008)
doi:10.1038/nri2216
PMid:18097448

127. V. Baud and M. Karin: Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov, 8(1), 33-40 (2009)
doi:10.1038/nrd2781
PMid:19116625    PMCid:2729321

128. A. Nencioni, F. Grunebach, F. Patrone, A. Ballestrero and P. Brossart: Proteasome inhibitors: antitumor effects and beyond. Leukemia, 21(1), 30-6 (2007)
doi:10.1038/sj.leu.2404444
PMid:17096016

129. G. Ayala, J. Yan, R. Li, Y. Ding, T. C. Thompson, M. P. Mims, T. G. Hayes, V. MacDonnell, R. G. Lynch, A. Frolov, B. J. Miles, T. M. Wheeler, J. W. Harper, M. J. Tsai, M. M. Ittmann and D. Kadmon: Bortezomib-mediated inhibition of steroid receptor coactivator-3 degradation leads to activated Akt. Clin Cancer Res, 14(22), 7511-8 (2008)
doi:10.1158/1078-0432.CCR-08-0839
PMid:19010869    PMCid:2820291

130. C. Aguilera, R. Hoya-Arias, G. Haegeman, L. Espinosa and A. Bigas: Recruitment of IkappaBalpha to the hes1 promoter is associated with transcriptional repression. Proc Natl Acad Sci U S A, 101(47), 16537-42 (2004)
doi:10.1073/pnas.0404429101
PMid:15536134    PMCid:534509

Key Words: NF-kappaB, Lung Cancer, Signaling, Prevention, Therapy, Review