Molecular Basis of Oncogenesis by NF-κB: From a Bird's Eye View to a RELevant Role in Cancer

Fan Y, Dutta J, Gupta N, et al.

Publication Details

The Rel/NF-κB transcription factors are renowned for their fundamental contribution to normal immune, inflammatory and acute phase responses. A growing body of evidence also underscores their important role in the control of cellular gene expression, cell proliferation and apoptosis. Thus, it comes as no surprise that sustained Rel/NF-κB activity has emerged as a hallmark of many human cancers. Experimental evidence indicates a strong correlation between the transcriptional activity of Rel/NF-κB and its role in malignant cell transformation. The important role of NF-κB in the control of the apoptotic response also supports its participation in the resistance of tumor cells to therapeutic treatment. This review focuses on the mechanisms that underlie the contribution of Rel/NF-κB to cancer and highlights how appreciation of its role in this context has evolved from a bird's eye view to a true recognition of its RELevant function in oncogenesis.

Introduction

The Rel/NF-κB transcription factors have been the focus of numerous studies aimed at elucidating their role in the development and function of the immune system and at unveiling the signaling pathways that control their activity (see accompanying chapters by M. Karin, S.C. Sun, R. Sen, U. Siebenlist, HC. Liou, Y. Chen, and C. Hunter). In recent years, there has been considerable progress in appreciating their contribution to oncogenesis and in understanding the mechanisms involved. Inappropriate Rel/NF-κB activity is observed in many different types of human cancers. Hyperactivation of the NF-κB signaling cascade, mutations that inactivate the inhibitory IκB subunits or chromosomal aberrations involving various rel/nf- κb genes have been noted in many human tumors.1,2 Consistent with the transforming activity of the viral Rel/NF-κB oncoprotein v-Rel and its cellular homologue c-Rel in primary cells and in animal models, NF-κB is also critically involved in malignant cell transformation by viruses such as the human T-cell leukemia virus type I (HTLV-1) and Epstein-Barr virus (EBV).3 Collectively, these findings justify the vast body of literature exploring the molecular basis for the role of Rel/NF-κB in cancer. Important findings center on its ability to regulate cellular gene expression, to affect cell proliferation and survival, and on important regulatory mechanisms that control its activity — all of which have important consequences for effective anti-cancer therapy.4-7

Constitutive Rel/NF-κB Activity Is a Hallmark of Many Human Cancers

Sustained activation of NF-κB is a feature of many human leukemia, lymphoma and solid tumors.1 Immunohistochemistry, gel mobility shift assays and gene expression profiling of primary tumor specimens and tumor-derived cell lines have highlighted the persistent nuclear localization of NF-κB subunits compared to normal controls (for example see refs. 8-11). The dimer comprised of the p50/p65 subunits is the most frequently reported NF-κB complex to be activated in human cancer, although there is evidence that clearly implicates c-Rel-containing complexes in certain tumor types, like breast cancer.8,9 The important implication of sustained NF-κB activity for the survival and proliferation of tumor cells is underscored by the growth arrest and rapid onset of apoptosis observed in many tumor-derived cell lines upon introduction of a degradation-resistant form of IκB (IκB super-repressor) to inhibit endogenous NF-κB activity (for example see refs. 12, 13).

Activation of the NF-κB Signaling Cascade

Persistent activation of the NF-κB pathway is observed in many different human cancers. By virtue of its ability to trigger the N-terminal phosphorylation of the NF-κB inhibitory subunit IκBα on serines 32 and 36, the IKK kinase complex promotes degradation of IκB via the ubiquitin/proteasome pathway. This enables NF-κB dimers to accumulate in the nucleus where they promote transcription of specific gene programs.14 Although the detailed mechanisms responsible for sustained IKK activation in many human tumors remain unknown, there are several potential mechanisms (Table 1).15,16

Table 1. Mechanisms for constitutive NF-κB activation in human cancer.

Table 1

Mechanisms for constitutive NF-κB activation in human cancer.

IKK Complex Activation

Since no mutation has yet been identified to affect IKK subunits in human tumors, unrelenting activation of NF-κB is likely to result from alterations in upstream signaling components. In many types of cancer, sustained IKK activation is achieved via autocrine loops involving cytokines and growth factors that activate the NF-κB pathway and are themselves transcriptional targets of NF-κB (Tables 1, 2).17 For instance, IL-1 activates NF-κB in pancreatic carcinoma cell lines and is in turn induced by NF-κB.18 Likewise CD40, the receptor for CD40 ligand, constitutively activates NF-κB in malignant Reed-Sternberg (H/RS) cells of Hodgkin's disease (HD) and is upregulated in these cells.19 Another mechanism for constitutive ctivation of the IKK complex involves deregulation of TRAF adaptor proteins in human tumors. TRAF2 is a critical component of receptor-triggered signaling pathways involving NF-κB, JNK and p38. Recent work showed that loss of the TRAF2- and IKKγ/NEMO-interacting tumor suppressor protein CYLD, a de-ubiquitinating enzyme for TRAF2, leads to constitutive activation of IKK coincident with increased cell resistance to apoptosis.20-23 Loss of CYLD causes cylindromatosis, an autosomal dominant syndrome that predisposes patients to benign tumors of hair follicles and sweat and scent glands.

Table 2. A sample of NF-κB-regulated gene products implicated in human cancer.

Table 2

A sample of NF-κB-regulated gene products implicated in human cancer.

Interestingly, recent work unveiled a new NF-κB-independent role for IKK in cancer. IKKβ expression in primary breast cancer specimens is correlated with poor survival and studies in primary breast cancer cell lines showed that IKK negatively regulates the forkhead transcription factor FOXO3a, independent of NF-κB activation.24 Indeed, IKK-mediated phosphorylation of FOXO3a promoted its nuclear export and proteolysis via the ubiquitin proteasome pathway to promote cell growth and tumorigenesis. It will be interesting to see if the newly reported abilities of IKKα and IKKγ/NEMO to localize to the nucleus and respectively modify histones and interact with CBP to regulate NF-κB gene expression imply that these subunits can also act on other nuclear targets to affect oncogenesis.25-27

Activation by Other Kinases, Oncogenes and Viruses

Other means to constitutively activate NF-κB signaling in human tumors entail various kinases other than IKK, as well as oncogenes and viruses (Table 1). One example involves the PI3-kinase to Akt kinase signaling pathway in response to overexpression of the epidermal growth factor (EGF) receptor family member c-erbB2/Her-2/Neu in breast cancer.28 IκBα degradation in this context is mediated by the protease calpain. Another example is casein kinase II (CKII) that phosphorylates serines in IκBα distinct from those targeted by IKK and triggers calpain-mediated cleavage of IκBα.29 Upregulation of CKII activity was suggested as a possible contributing factor to hepatocarcinoma induced by TGF-β1.30

A number of oncogenes mediate their transforming function by virtue of NF-κB activation. These include the chimeric oncoprotein tyrosine kinase Bcr-Abl implicated in acute lymphocytic leukemia (ALL) and chronic myelogenous leukemia (CML), and the Ras oncogene. Bcr-Abl enhances nuclear translocation of NF-κB and the transactivation function of NF-κB subunit p65/RelA via MEKK1 and p38 MAPK and also partially requires Ras function.31-33 Ras is another well-known oncogene mutated in human tumors that utilizes NF-κB to achieve oncogenesis.34,35 The anti-oncogenic effect of lysyl oxidase on Ras-transformed cells was recently demonstrated to involve suppression of NF-κB activation.36 An interesting new report showed that the API2/MALT1, a chimeric protein between inhibitor of apoptosis c-IAP2 and the MALT1 paracaspase, participates in the transformation process of mucosa-associated lymphoid tissue (MALT) lymphoma by activating NF-κB dimers comprised of RelB/p50.37 It will be interesting to see whether other oncogenes act in a similar manner.

Lastly, many viruses achieve their oncogenic effects via the NF-κB signaling cascade (Table 1). 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-κB by HTLV-1 Tax causes nuclear accumulation of NF-κB dimers, helps to overcome their inhibition by the p105/ NF-κB1 subunit, and is an essential step in the transformation of T cells.38-41 Additionally, Tax stimulates phosphorylation-dependent processing of NF-κB2/p100, and hence activates both the canonical and noncanonical NF-κB pathways.42 Another virus that contributes to human cancer via NF-κB 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-κB activity thereby preventing apoptosis in EBV-transformed B cells.41,43 This is consistent with the ability of LMP-1 to induce expression of NF-κB-dependent anti-apoptotic proteins such as Bfl-1/A1.44,45 Akin to Tax, LMP-1 induces proteolytic processing of p100/ NF-κB2 to its p52 form, consistent with the high levels of p52 found in Hodgkin's lymphoma and nasopharyngeal carcinoma from EBV-infected patients.46,47

iκB Gene Mutations

Although much less frequent than upstream activation of the NF-κB pathway, there have been a few reports of iκB gene mutations implicated in constitutively activating NF-κB in human tumors. Mutations that suppress the inhibitory activity of IκBα or IκBε were observed in some Hodgkin's lymphomas and a large B-cell lymphoma cell line (Table 1).48-53 The fact that bi-allelic mutation was needed for IκBα loss-of-function in Hodgkin's lymphoma raised the suggestion that it may act as a tumor suppressor.

nf-κB Gene Rearrangement, Amplification and/or Overexpression in Human Cancer

While sustained activation of NF-κB signaling is the most common mode of NF-κB activation in human tumors, there are a number of cases in which rel/nf-κB gene amplification, rearrangement and/or overexpression was documented (Table 1).1 The majority of human rel and nf-κB genes (i.e., c-rel, relA, nf-κb1 and nf-κb2) have been targeted in this fashion, although nf-κb2 and c-rel are the most commonly affected.

Chromosomal rearrangements disrupting the 3' coding region of the nf-κb2 gene are frequently observed in cutaneous T-cell lymphoma and also in a small number of B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia and multiple myeloma.54-58 The resulting C-terminally truncated p100/NF-κB2 proteins primarily localize to nuclei and bind to NF-κB DNA motifs. However, how tumor-derived truncated p100 proteins contribute to oncogenesis remains to be clarified. Loss of the C-terminal ankyrin motifs in tumor-derived p100 mutants was proposed to abolish the IκB-like function of p100, resulting in abnormal NF-κB activity. A more recent study suggested another mechanism for oncogenic activation, i.e., that loss of a putative C-terminal death domain in tumor-derived p100 mutants might abrogate a proapoptotic effect of p100,59 although this has been a subject of debate.60 It is interesting to note that homozygous deletion of the C-terminal ankyrin repeats of p100 leads to gastric and lymph node hyperplasia in mice, suggesting that overexpression of p52/NF-κB2 contributes to oncogenesis.61-63 In support of this hypothesis, tumor-derived rearranged p100 proteins undergo constitutive processing to produce functional p52, due to deletion of a C-terminal processing-inhibitory domain (PID).64 Moreover, overexpression of p52 was detected in several malignancies including T-cell leukemia and breast and colon carcinoma.9,65,66 The ability of p52 homodimers to function as transcriptional activators in combination with RelB or the IκB-related Bcl-3 transcription factor to promote expression of antiapoptotic and proproliferative genes such as bcl-2 and cyclin D1 is consistent with this model.9,67

The human c-rel locus is amplified in a significant proportion of diffuse lymphoma with a large cell component (DLLC; 23%) and also in primary mediastinal (thymic) B-cell lymphoma, classical Hodgkin's lymphoma and certain follicular large cell lymphoma.1 However, the extent to which c-rel gene amplification causes elevated nuclear c-Rel protein levels is unclear. While some found a correlation between amplification of the c-rel locus and nuclear c-Rel protein accumulation in Hodgkin's lymphoma and mediastinal large B-cell lymphoma (MLBCL),68,69 others found no close association between the two or with NF-κB target gene expression profiles in diffuse large B cell lymphoma (DLBCL).70,71 These findings suggest that if c-rel plays a role, its function may be heterogeneous in different lymphomas or that it might play a role early in the history of some of these tumors that is no longer required later on. Although c-rel's contribution to some of these tumors remains a point of contention,72 future studies will undoubtedly provide important information on the subject.

Molecular Basis for Oncogenesis by Rel/NF-κB

Studies with the retroviral NF-κB oncoprotein v-Rel and its cellular Rel/NF-κB homologues have provided important insights into the oncogenic properties of Rel/NF-κB factors and the functional mechanisms involved. These are reviewed in this section.

The Viral NF-κB Oncoprotein v-Rel: A Potent Transforming Factor

Evidence pointing to a role for Rel/NF-κB in cancer came about long before the discovery of the rel/nf-κb gene family, with the isolation in 1958 of the Rev-T retrovirus from the liver of a diseased turkey.73,74 The culprit Rev-T-encoded oncogene was identified many years later as v-rel, the first member of the Rel/NF-κB family.75 v-rel immortalizes and transforms immature and mature B and T lymphoid, myeloid and dendritic cells from chicken spleen and bone marrow and induces aggressive and fatal leukemia/lymphoma in infected young birds.76-79 v-Rel can also transform chicken embryo fibroblasts that induce tumors in immunocompetent young chicks.80

The oncogenic activity of v-rel was believed for some time to be restricted to avian species, as efforts to stably express it in rodent fibroblasts or lymphoid B cells resulted in apparent cytotoxicity.81-83 Although the molecular basis for this effect remains to be clarified, stable expression was recently achieved in mouse fibroblasts using a mouse stem cell virus (MSCV),84 but it remains to be seen if MSCV-driven v-rel will be transforming in mouse lymphoid cells. Yet, the discovery that transgenic mice expressing v-rel under the control of the lck promoter developed aggressive T-cell leukemia/lymphoma provided unambiguous proof of its oncogenic potential in mammals.85 It is noteworthy however that the onset of tumor development in transgenic mice is remarkably slower than in infected chickens, with mice succumbing between 6 to 10 months of age compared to 7 to 10 days in young chicks. Another distinction between the avian and mammalian systems is the fact that tumors arising in v-rel transgenic mice are oligoclonal, rather than polyclonal in nature, and that they fail to transplant in syngeneic animals.85 This suggests that additional cytogenetic alterations are necessary for manifestation of v-rel's tumorigenic potential in mammals. In this regard, chickens lack p16INK4a and express a truncated but functional ARF protein.86 This raises the possibility that tumor suppressors such as those encoded by the ink4b-arf-ink4a locus perhaps contribute to the increased susceptibility of chickens to v-rel-induced transformation. Nevertheless, in light of the rapidly increasing number of studies implicating Rel/NF-κB activity in human tumors, v-rel is a highly prized tool to unravel the molecular basis for the oncogenic activity of cellular Rel/ NF-κB factors.

A Role for c-Rel in Cell Transformation and Tumorigenesis: Lessons from Birds and Mice

Since v-rel arose by recombination of the non-transforming Rev-A retrovirus with the turkey c-rel proto-oncogene, it is not surprising to find that overexpression of the chicken, mouse or human c-rel genes transforms primary chicken cells in culture that induced tumor development in animal models, albeit at a lower efficiency than v-rel.87-91 However when tested under similar conditions, other mammalian Rel/NF-κB subunits namely RelA, RelB, p50/NF-κB1 or p52/NF-κB2 failed to transform lymphoid cells.87 Together, these findings suggest that overexpression of the c-Rel protein in some tumors showing c-rel gene amplification and/or constitutive activation of c-Rel-containing NF-κB complexes might contribute to certain human leukemia/lymphoma.

Importantly, c-rel was recently shown to also exhibit an oncogenic capacity in a mammalian system. Indeed, 31% of transgenic mice expressing the mouse c-rel gene under the control of the mouse mammary tumor virus (MMTV) promoter developed mammary tumors at an average age of 19.9 months.92 Tumor development coincided with nuclear localization of NF-κB subunits and upregulation of many NF-κB-target genes including cyclin D1, c-myc, and bcl-xl (Table 2; see below). The significance of these findings is highlighted by the fact that many human breast cancer specimens show elevated NF-κB activity.8,9,93-95

Rel/NF-κB Functions Necessary for Cell Transformation

As a result of its acquisition and evolution in the context of the Rev-T retrovirus, v-rel encodes a truncated and mutated version of the turkey c-Rel protein fused to remnants of the Rev-A retroviral env gene. v-Rel carries a number of deletions and point mutations compared to c-Rel, including the loss of 118 C-terminal amino acids that correspond to a strong transactivation domain (TAD) in c-Rel.74 Many of these differences contribute to the increased oncogenicity of v-Rel compared to c-Rel. For example selection for C-terminal truncation of c-Rel, reminiscent of that seen in v-Rel, was observed in tumors that arose following retroviral-mediated delivery of c-rel into young chickens.96 Recent work from our group indicates that c-rel gene deletion or mutation is not necessary for lymphoid cell transformation “per se”, but that it may rather be selected for during tumor progression to confer enhanced tumorigenicity, enable escape from immune surveillance and/or facilitate cell adaptation to growth in culture.87

A model for v-Rel-mediated oncogenesis has emerged that invokes its ability to transactivate κB site-dependent gene transcription as being critical for cell transformation. Mutations that decrease its DNA-binding or transactivation functions are detrimental to cell transformation, whereas those that increase these activities enhance its transforming potential.97-106 Consistent with this model, v-Rel shuttles between the nucleus and the cytoplasm, and a threshold of nuclear v-Rel is necessary to transform cells.107 Other factors also contribute to the enhanced oncogenicity of v-Rel compared to c-Rel.74 These include the fact that: (1) v-Rel is less susceptible than c-Rel to inhibition by IκBα.108,109 This agrees with the partial nuclear distribution of v-Rel/IκBα complexes compared to predominantly cytoplasmic NF-κB/IκBα complexes in unstimulated cells.110,111 Despite its reduced susceptibility to inhibition by IκBα, v-Rel is nevertheless subject to IκBα control, as overexpression of IκBα in v-rel transgenic mice attenuated its tumorigenic phenotype.112 (2) v-Rel binds to a broader range of NF-κB DNA sites compared to c-Rel and other NF-κB subunits. Nehyba et al identified mutation clusters in v-Rel responsible for this difference, and Phelps and Ghosh recently pinpointed amino acid differences between the Rel-homology domains (RHDs) of v-Rel and c-Rel in this effect.109,113 (3) The particular dimers in which v-Rel participates also dictate its oncogenic potential. Mutational analysis revealed a critical role for v-Rel homodimers in cell transformation.114 Although v-Rel/p50 heterodimers and v-Rel homodimers are the major DNA-binding complexes in v-rel transgenic mice, transgenic expression of v-rel in a p50 knockout background led to a more aggressive tumor phenotype.85 (4) Recent work from our group indicated that critical determinants for the different oncogenic potentials of individual Rel/NF-κB subunits reside within their divergent TADs.87 While RelA fails to transform primary chicken spleen cells, substitution of its TAD by that of the transforming v-Rel or c-Rel proteins conferred a strong transforming phenotype both in vitro and in vivo. Intrinsic differences between individual Rel/NF-κB TADs might confer distinct oncogenic potentials owing to differences in the repertoire of genes that they activate, as suggested by preliminary microarray analyses (Gupta, Fan, Delrow and Gélinas, unpublished data). Furthermore, the strength of individual Rel/NF-κB TADs is inversely correlated with their transforming potential, indicating that the magnitude of gene activation must be within a suitable range. For example, deletion of either of the two human c-Rel TADs reduced its transcriptional activity and increased its transforming efficiency.115 Since strong TADs such as that of RelA perhaps activate gene expression to a level that is incompatible with cell transformation, it is tempting to speculate that RelA mutants with decreased transactivation potency might be capable of transformation. Preliminary data from our group suggest that this may indeed be the case (Fan and Gélinas, unpublished data). Overall, these findings underscore a fundamental role for gene transactivation in the transforming ability of Rel/NF-κB.

Functional Consequences of Rel/NF-κB-Mediated Gene Activation in Oncogenesis

The Rel/NF-κB transcription factors activate a wide variety of target genes that influence its oncogenicity. These include cell death inhibitors, cell cycle regulators, transcription factors and oncoproteins, cytokines and receptors, and cell surface and adhesion molecules. This section reviews how these contribute to the transformation process by affecting the regulation of apoptosis, cell proliferation, angiogenesis and metastasis.

Suppression of Apoptosis

Escape from apoptosis is a major factor in oncogenesis and in the resistance of tumor cells to therapy. It is therefore not surprising that NF-κB's anti-apoptotic activity has been linked to many different cancers and that it impedes effective treatment.116, 117 Consistent with the fact that Rel/NF-κB inhibits cell death by activating expression of antiapoptotic genes that can at least partially substitute for NF-κB to suppress cell death, many tumor-derived cell lines display elevated expression of NF-κB-dependent antiapoptotic factors (Table 2).4 For instance, therapy-resistant DLBCL tumors and malignant H/RS cells have elevated levels of bfl-1/a1 transcripts compared to controls, and FLIP is upregulated in DLBCL while c-iap2 is induced in H/RS cells.11, 19, 71, 118 The important role for NF-κB in these cancers is highlighted by the fact that many tumor-derived cell lines, including those derived from HD, DLBCL and breast cancer undergo spontaneous apoptosis, or are sensitized to death-inducing stimuli, following NF-κB inhibition (for example see refs. 6,8,12,13,119-121). Although ectopic expression of Bcl-xL could rescue apoptosis of H/RS cells in which NF-κB activity was suppressed,19 it should be noted that in other cases multiple apoptosis inhibitors appear to act in concert to promote survival in NF-κB-associated tumors.12 These findings agree with the observation that sustained expression of v-rel is necessary to maintain the viability of transformed lymphoid cells and that v-rel-mediated transformation requires expression of specific apoptosis inhibitors (Table 2).100,106,122-127 Though a majority of studies emphasize a fundamental role for the cytoprotective activity of NF-κB in oncogenesis, there are exceptions. For instance, survival in Bcr-Abl-induced leukemia was reported to be independent of NF-κB's antiapoptotic activity.31

Alternative mechanisms have emerged in which NF-κB promotes cell viability by interacting with other factors. For example, NF-κB interferes with the transcriptional function of the pro-apoptotic tumor suppressor p53 by competing for coactivators.128-130 Similarly, p65/RelA sequesters coactivator p300 to inhibit expression of tumor suppressor PTEN and allow cell survival in lung and thyroid cancer cells.131 The recently discovered capacity of IKKβ to increase expression of Mdm2 and decrease p53 stability to suppress chemotherapy-induced cell death is another example.132 Lastly, NF-κB-mediated suppression of the p53-related p73 factor antagonizes apoptosis in antigen-stimulated naïve T cells.133 This raises the possibility that a similar mechanism might operate in an oncogenic setting, although this remains to be established.

Cell Proliferation

Independent studies highlight a link between Rel/NF-κB's effects on cell proliferation and oncogenesis. Consistent with the critical role of the c-Rel subunit in B cell proliferation,134,135 lymphoid cells transformed by a temperature-sensitive mutant of v-Rel fail to proliferate at the restrictive temperature under conditions where apoptosis is rescued by cell death inhibitor Bcl-2.127 Aside from generating autocrine loops to constitutively activate the NF-κB pathway in tumor cells (see above), NF-κB activates expression of factors that influence cell cycle entry such as cyclins D1, D2 and D3 (Table 2).19,135-137 These findings concur with the elevated levels of cyclin D2 in malignant H/RS cells and cyclin D1 in mantle cell lymphoma and breast cancers that display sustained NF-κB activity, as well as in MMTV-c-rel-induced mouse mammary carcinoma.19,92,138

NF-κB can also enhance proliferation by activating other transcription factors. Some of them directly contribute to v-Rel-mediated transformation of lymphoid cells (Table 2). For example transcription factor AP-1(c-Jun) is essential for v-Rel's transforming activity in primary lymphoid cells and fibroblasts.139 Both c-Jun and JunB are aberrantly expressed in malignant H/RS cells of HD, where upregulation of JunB is NF-κB-dependent.140 These factors act together with NF-κB to stimulate H/RS cell proliferation and expression of cyclin D2, Bcl-xL, c-met and chemokine receptor CCR7. Other examples are interferon regulatory factor 4 (IRF 4) that decreases induction of the anti-proliferative IFN pathway and facilitates v-Rel-mediated transformation141 and c-Myc, a target of p50/c-Rel dimers that is induced in MMTV-c-rel mouse mammary tumors.92,142 Stat5a recently joined this group as an NF-κB target that is activated constitutively in HD and is linked to cell growth regulation.10

Angiogenesis and Metastasis

The ability of tumor cells to acquire sustained angiogenesis, invade surrounding tissues and metastasize to remote sites is one of the most significant factors contributing to cancer patient mortality. Here too NF-κB makes an important contribution by inducing expression of factors that promote angiogenesis (Table 2). Elevated NF-κB activity in cancer cells enables deregulated production of chemokines and chemokine receptors, like IL-8 and CXCR4, which increase migratory activity and promote angiogenesis.143,144 NF-κB-mediated induction of vascular endothelial growth factor (VEGF) is another important contributing factor.144,145 NF-κB also promotes invasion of surrounding tissues by inducing various cell adhesion molecules and matrix metalloproteinases.7,145 Together, these factors contribute to the pathogenesis of NF-κB in cancer.

Other Means for NF-κB to Participate in Oncogenesis

Several protein interactions and post-translational modifications modulate the transcriptional activity of NF-κB, and in some cases its contribution to oncogenesis.

Interaction with Transcription Factors and Coactivators

v-Rel and its cellular homologues c-Rel and RelA functionally interact with basal transcription factors and transcriptional coactivators to synergistically enhance gene transcription (for example see refs. 146-148). In some instances, interactions were confirmed in transformed lymphoid cells.146 Although various coactivators like CBP/p300, TAFII105 or TAFII250 mediate NF-κB dependent transcription of anti-apoptotic genes, their implication in a tumor context is awaiting.149-153 However PARP (Poly-ADP ribose polymerase-1) that behaves as a coactivator for NF-κB was recently implicated in NF-κB-mediated susceptibility to skin cancer induced by DMBA and TPA in mice but their coordinate action in human carcinogenesis remains to be verified.154,155

Post-Translational Modifications

Phosphorylation, acetylation and ubiquitination of NF-κB subunits influence their activity, although in many cases evidence of their role in NF-κB-associated tumors has yet to be obtained.

Various kinases including IKK, casein kinase II and AKT enhance the transcriptional activities of p65/RelA and c-Rel by phosphorylating their TAD.156-162 Moreover, mutation of certain serines in the v-Rel TAD decreases its transcriptional activity and impairs transformation of lymphoid cells.106 In addition, the catalytic subunit of PKA (PKAc), MSK1 and PKCη phosphorylate the RHD of p65/RelA and modification by PKAc is necessary for p65 interaction with coactivator p300.163-166 Of interest, serine phosphorylation in the C-terminal domain of Bcl-3 by GSK3 affects its interaction with HDACs and is correlated with attenuation of its transforming potential in a mouse model.167 Acetylation bestows another level of regulation, as exemplified by reversible p300/CBP- and P/CAF-mediated acetylation of p65/RelA that blocks association with IκBa and promotes p65 nuclear localization, DNA binding, and transactivation.168-171

A role for the ubiquitin-proteasome pathway in directly regulating the stability of NF-κB subunits came to light in work showing that C-terminally truncated c-Rel mutants and v-Rel display reduced proteasome-mediated turnover coincident with oncogenic transformation.172 Since then, poly-ubiquitination of p65/RelA was implicated in terminating the NF-κB response.173 In this regard, the peptidyl-prolyl isomerase Pin1 was recently described to enhance NF-κB activity by associating with nuclear p65 to prevent its SOCS-1-mediated ubiquitination and degradation.174 The fact that Pin1 is highly overexpressed in human breast cancer suggests a possible role for Pin1 in enhancing the oncogenic activity of NF-κB in certain tumors.

A Tumor Suppressor Role for NF-κB

Despite a large body of evidence supporting a positive role for Rel/NF-κB in oncogenesis, a growing number of studies indicate that NF-κB can behave as a tumor suppressor in some circumstances.175,176 Indeed RelA opposes the action of TNFR1 and JNK to curb epidermal cell growth, and suppression of NF-κB in skin cooperates with oncogenic lesions such as oncogenic Ras to favor development of squamous cell carcinoma.177-181 Consistent with this, immortalized relA-/- fibroblasts induce tumors in SCID mice.182 Moreover, RelA actively represses transcription of anti-apoptotic genes in response to certain stimuli such as UV-C and chemotherapeutic agents doxorubicin or daunorubicin,183 although others found NF-κB to be protective in this context.184,185

The interaction of NF-κB with tumor suppressors to downregulate proproliferative or antiapoptotic genes, or to induce expression of pro-death factors further supports the notion that NF-κB can inhibit tumor growth in certain settings (Table 2). ARF, best known for its role in activating p53 via inhibition of Mdm2, inhibits p65/RelA-mediated transcription by inducing p65 association with histone deacetylase HDAC1.186 This effect is promoter specific, as it leads to downregulation of anti-apoptotic NF-κB target Bcl-xL but not IκBa. Similarly, tumor suppressor p53 converts transcriptionally active Bcl-3/p52 complexes into transcriptionally inactive p52/HDAC1 complexes that inhibit cyclin D1 expression to induce cell cycle arrest.187 The significance of these findings is highlighted by the observation that c-Rel, p52 and Bcl-3 are activated in human breast cancer.9,95 Interestingly, tumor suppressor BRCA1 physically interacts with p65/RelA to enhance NF-κB-mediated transcription of proapoptotic gene Fas, while ING4 controls brain tumor angiogenesis by negatively regulating RelA's transcriptional activity.188,189 Lastly, NF-κB was reported to be required for p53-dependent apoptosis,190 and recent work implicated the serine/threonine kinase ribosomal S6 kinase 1 (RSK1) in its p53-mediated activation.191 While one study found that NF-κB activation by doxorubicin decreases p53 stability,132 another showed that NF-κB stabilizes p53 to provoke apoptosis in response to genotoxic stress.192 Regardless of the mechanisms involved, the capacity of NF-κB to sometimes behave as a tumor suppressor has obvious implications for its role in oncogenesis and for therapeutic approaches aimed at inhibiting its activity (see below).

Conclusions and Perspectives for Therapy

While additional work is needed to pinpoint the precise role of Rel/NF-κB in human cancer and the mechanisms involved, a parallel has emerged between activities needed for lymphoid cell transformation and lymphomagenesis induced by the v-Rel and c-Rel proteins and those observed in many human tumors displaying constitutive NF-κB activity. These include inappropriate activation of cellular gene expression and aberrant expression of proproliferative and antiapoptotic genes. While the Rel proteins are potently oncogenic in avian species, the delayed onset of tumors in transgenic mice expressing v-rel or an MMTV-c-rel transgene suggests that additional cytogenetic alterations are necessary for NF-κB to manifest its oncogenic phenotype in mammals.85,92 Recent studies uncovered a crucial role for interaction between inflammatory cells and precancerous cells in tumor promotion and showed that NF-κB is critical in this process.193-195 Thus, identification of the genes and pathways that act cooperatively with NF-κB in human cancer is an important goal in the field.

The NF-κB pathway constitutes an important therapeutic target.145 NF-κB is implicated in the intrinsic resistance of cancer cells to apoptosis and the induced chemoresistance of many tumors to anti-cancer drugs, and its inhibition often enhances the effectiveness of treatment (for example see refs. 119, 121, 184). However recent advances uncovered a more complex scenario, by revealing that NF-κB can sometimes repress transcription of anti-apoptotic genes in response to “atypical” activators including several chemotherapeutic agents.175,183 Its interaction with tumor suppressors such as p53, ARF and BRCA1 is another potentially important factor in the outcome of cancer therapy. Careful attention should thus be given to the tumor cell type, the death-inducing agent and perhaps other cytogenetic alterations in these tumors. Ongoing studies in the field promise to further advance our understanding of the transcriptional, anti-/pro-proliferative and anti/pro-apoptotic functions of NF-κB, the modifications and factors that modulate its activity and their impact on the oncogenic process. Together these will help to develop and improve appropriate strategies for cancer therapy tailored to particular contexts.

Acknowledgments

We are very grateful to N. Perkins for sharing a review article before publication. We apologize to many investigators whose work could not be cited due to space limitations. Research in this laboratory on the roles of Rel/NF-κB and its anti-apoptotic target Bfl-1/A1 in apoptosis and oncogenesis is supported by grants from the National Institutes of Health — National Cancer Institute CA54999 and CA83937 to CG. The first three authors contributed equally to this review.

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