Nuclear factor-kappa B and cancer: its role in prevention and therapy

https://doi.org/10.1016/S0006-2952(02)01154-1Get rights and content

Abstract

Cancer is a hyperproliferative disorder in which invasion and angiogenesis lead to tumor metastasis. Several genes that mediate tumorigenesis and metastasis are regulated by a nuclear transcription factor, nuclear factor kappa B (NF-κB). A heterotrimeric complex consisting of p50, p65, and IκBα, NF-κB is present in its inactive state in the cytoplasm. When NF-κB is activated, IκBα is degraded and p50–p65 heterodimer is translocated to the nucleus, binds the DNA (at the promoter region), and activates gene. Research within the last few years has revealed that NF-κB is activated by carcinogens, tumor promoters, inflammatory cytokines, and by chemotherapeutic agents. The activation of NF-κB can suppress apoptosis, thus promoting chemoresistance and tumorigenesis. Interestingly, however, most chemopreventive agents appear to suppress the activation of the NF-κB through inhibition of NF-κB signaling pathway. These chemopreventive agents also sensitize the tumors to chemotherapeutic agents through abrogation of NF-κB activation. Overall, these observations suggest that NF-κB is an ideal target for chemoprevention and chemosensitization. This article reviews evidence supporting this hypothesis.

Introduction

From extensive research during last half of the century, the common saying that “you are what you eat” is becoming increasingly accepted. To prevent the onset of both cancer and cardiovascular diseases, the National Institute of Health in the United States has recommended a high-fiber, low-fat diet, consisting of more fruits and vegetables. The importance of the diet is further suggested by the epidemiological evidence that certain cancers (e.g. breast, prostate, colon, and lung) are more prevalent in the developed countries than in the developing countries, most likely because of differences in dietary constituents. The molecular mechanism by which diet mediates its preventive and therapeutic effects is an active area of current research. We propose that there are constituents of the every-day diet that regulate the activity of certain transcription factors such as NF-κB that play a critical role in carcinogenesis.

NF-κB is a transcription factor discovered by Sen and Baltimore in 1986, in the kappa light chain of immunoglobulins in B cells [1]. Research over the last few years has revealed that NF-κB is an inducible and ubiquitously expressed transcription factor for genes involved in cell survival, cell adhesion, inflammation, differentiation, and growth [2], [3], [4], [5]. Active NF-κB complexes are dimers of various combinations of the Rel family of polypeptides consisting of p50 (NF-κB1), p52 (NF-κB2), c-Rel, v-rel, Rel A (p65), and Rel B (see [6], [7]). These proteins share a conserved 300 amino acid region within their amino termini, termed RHD, that is responsible for DNA binding, dimerization, nuclear translocation, and interaction with heterologous transcription factors. Although all Rel family members bind to DNA, only p65, c-Rel, and RelB contain a transactivation domain. In most resting cells, NF-κB is retained in the cytoplasm by binding to the inhibitory IκB proteins (IκBα, IκBβ, IκBε, p105, and p100), which blocks the nuclear localization sequences of NF-κB [8]. NF-κB is activated in response to a wide variety of stimuli that promote the dissociation of the IκBα through phosphorylation, ubiquitination, and degradation, thus unmasking of the nuclear localization sequence of NF-κB thereby allowing NF-κB to enter the nucleus and bind κB-regulatory elements [9]. The phosphorylation of IκBα is a critical step in the pathway leading to NF-κB activation, and this step is catalyzed by an IκBα kinase (IKK) complex (molecular mass of 700 kDa) consisting of IKK-α, IKK-β, IKK-γ (also called NEMO), and other proteins yet to be identified [10].

Because of the critical role of NF-κB in cell survival, cell adhesion, inflammation, differentiation, and cell growth, it has been implicated in carcinogenesis. Cancer is a hyperproliferative disorder that results from tumor initiation and tumor promotion, which ultimately produces tumor metastasis. Several genes that are involved in cellular transformation, proliferation, invasion, and angiogenesis are regulated by NF-κB [11], [12]. The focus of this review is to present the evidence that NF-κB can lead to tumorigenesis and, therefore, establishes that agents that suppress NF-κB can abrogate carcinogenesis. We also present evidence that suppression of NF-κB can sensitize tumor cells to chemotherapeutic agents.

Several recent studies indicate that NF-κB is activated by various carcinogens and tumor promoters. These include benzo[a]pyrene, NNK, UV radiation, and phorbol esters [9], [13], [14], [15], [16]. For instance UV radiation has been shown to cause sunburn reactions (swelling, leukocyte infiltration, epidermal hyperplasia, and accumulation of proinflammatory cytokines) leading to skin cancer, and suppression of NF-κB blocks the sunburn-induced damage [17].

In 1996, four independent reports showed that activation of NF-κB promotes cell survival and downregulation of NF-κB sensitizes the cells to apoptosis induced by cytokines and chemotherapeutic agents [18], [19], [20], [21]. How NF-κB activation promotes cell survival is becoming increasingly clear. The expression of several genes including bcl-2, bcl-xL, cIAP, xIAP, TRAF1, TRAF2, SOD, and A20, have been reported to be regulated by NF-κB and to mediate cell survival (Table 1). How these proteins enhance cell survival is not fully understood, but their role in blocking the apoptosis pathway has been demonstrated [3]. Studies from our laboratory and others have shown that expression of activated NF-κB promotes cell proliferation and suppression of NF-κB leads to abrogation of proliferation [22], [23], [24].

Invasion and angiogenesis are critical events for tumor metastasis. Various genes that are involved in tumor cell invasion and angiogenesis have also been found to be regulated by NF-κB. These include the cell adhesion molecules (ICAM-1, VCAM-1, ELAM-1), COX2, iNOS, uPA, MMP-9, MMP-2, VEGF, chemokines, and inflammatory cytokines (Table 2). Thus, the suppression of NF-κB activation will likely abrogate the expression of these genes and, thus, prevent tumor metastasis.

While it is clear from these description that NF-κB is needed for tumor cell proliferation, invasion, and angiogenesis, tumor cells have been found to constitutively express the activated form of NF-κB. Several different tumor cell types, including leukemia, lymphoma, myeloma, melanoma, prostate, colon, breast, pancreas, and head and neck squamous cell carcinoma cell lines have been reported to express constitutively active NF-κB [23], [25], [26], [27]. We and others have shown that samples obtained from cancer patients also exhibit constitutive NF-κB [24]. What causes the constitutive activation of NF-κB is not fully understood, but the roles of TNF, IL-1, pH, and hypoxia has been demonstrated. Our laboratory has shown that constitutive NF-κB in T cell cutaneous lymphoma [28] and in acute myelogenous leukemia [29] is due to constitutive expression of TNF and IL-1, respectively. Suppression of TNF and IL-1 production was found to downregulate the expression of active NF-κB, which correlated with inhibition of proliferation of these tumor cells.

How chemopreventive agents suppress tumorigenesis is not fully understood. Several assays have been developed to determine the chemopreventive ability of an agent [30]. We have noted that most agents that have chemopreventive effects suppress the activation of NF-κB. These include curcumin, resveratrol, emodin, green tea polyphenols, silymarin, β-lapachone, caffeic acid phenethyl ester, and sulindac (Table 3). Since NF-κB regulates the expression of numerous genes that are involved in carcingenesis (Table 2), the suppression of expression of these genes through inhibition of NF-κB activation may be one of the mechanisms by which chemopreventive agents mediate their effects.

It has been found that most chemotherapeutic agents activate NF-κB. These include taxol, doxorubicin, daunorubicin, etoposide, vincristin, vinblastin, ara-C, anthralin, AZT, ciprofirate, cisplatin, haloperidol, methamphetamine, phenobarbital, temoxifen, and camptothecin [9]. Even gamma irradiation, commonly used to treat cancer patients, has also been found to activate NF-κB [31]. The activation of NF-κB can lead to resistance to apoptosis ordinarily induced by chemotherapy or radiation therapy. Thus, while activating apoptosis, the same agent can also activate NF-κB, which can lead to antiapoptosis.

Most chemotherapeutic agents and ionizing radiation induce apoptosis through activation of various caspases. They also activate antiapoptosis through activation of NF-κB, which leads to eventual resistance of tumor cells to therapy. Since most chemotherapeutic agents are known to suppress the activation of NF-κB and NF-κB-regulated gene expression, we propose the use of chemotherapeutic agents or gamma radiation in combination with chemopreventive agents for the therapy of cancer (Fig. 1). Besides blocking NF-κB activation, chemopreventive agents such as curcumin and resveratrol are also known to induce apoptosis [23], [32], [33]. Thus, unlike chemotherapeutic agents, chemopreventive agents induce apoptosis without activating the antiapoptosis pathway. Because most chemopreventive agents are natural plant-derived products, there is minimum toxicity associated with them. This provides an additional rationale for combination therapy.

Section snippets

Conclusions

Evidence presented above suggests that activation of NF-κB can lead to tumor cell proliferation, invasion, angiogenesis, and metastasis. Thus, suppression of NF-κB in cancer cells may provide an additional target for prevention of cancer. NF-κB blockers can also be considered for the therapy of cancer, perhaps in combination with chemotherapeutic agents or gamma irradiation. Cancer is a multifactorial disease, and its treatment may also require multimodal therapy. In most instances when the

Acknowledgements

This research was supported by grants from the Clayton Foundation, National Institute of Health (1P01 CA91844-1), and by the Department of Defense (BC010610) to BBA. We will like to thank Walter Pagel for a careful review of the manuscript.

References (71)

  • S.S. Han et al.

    Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53

    Clin. Immunol.

    (1999)
  • M.V. Clement et al.

    Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells

    Blood

    (1998)
  • S. Nasi et al.

    Making decisions through Myc

    FEBS Lett.

    (2001)
  • M.M. Chan et al.

    In vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural product with anti-inflammatory properties

    Biochem. Pharmacol.

    (1998)
  • S. Philip et al.

    Osteopontin stimulates tumor growth and activation of promatrix metalloproteinase-2 through nuclear factor-kappa B-mediated induction of membrane type 1 matrix metalloproteinase in murine melanoma cells

    J. Biol. Chem

    (2001)
  • E. Heiss et al.

    Nuclear factor kappa B is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms

    J. Biol. Chem.

    (2001)
  • M. Kunz et al.

    Anoxia-induced up-regulation of interleukin-8 in human malignant melanoma. A potential mechanism for high tumor aggressiveness

    Am. J. Pathol.

    (1999)
  • D. Delia et al.

    Regulation of apoptosis induced by the retinoid N-(4-hydroxyphenyl) retinamide and effect of deregulated bcl-2

    Blood

    (1995)
  • K. Natarajan et al.

    Protein tyrosine kinase inhibitors block tumor necrosis factor-induced activation of nuclear factor-kappaB, degradation of IkappaBalpha, nuclear translocation of p65 and subsequent gene expression

    Arch. Biochem. Biophys.

    (1998)
  • S.K. Manna et al.

    Suppression of tumor necrosis factor-activated nuclear transcription factor-kappaB activator protein-1, c-Jun N-terminal kinase and apoptosis by beta-lapachone

    Biochem. Pharmacol.

    (1999)
  • Y. Yamamoto et al.

    Sulindac inhibits activation of the NF-kappaB pathway

    J. Biol. Chem.

    (1999)
  • S.K. Manna et al.

    Wortmannin inhibits activation of nuclear transcription factors NF-kappaB and activated protein-1 induced by lipopolysaccharide and phorbol ester

    FEBS Lett.

    (2000)
  • Aggarwal BB, Vilcek J. Tumor necrosis factor: structure, function and mechanism of action. New York: Marcel Dekker Inc,...
  • Shishodia S, Aggarwal BB. Nuclear factor-kappa B activation: a question of life and death. J Biochem Mol Biol...
  • T. Collins et al.

    Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers

    FASEB J.

    (1995)
  • A.S. Baldwin

    The NF-kappa B and I kappa B proteins: new discoveries and insights

    Annu. Rev. Immunol.

    (1996)
  • H.L. Pahl

    Activators and target genes of Rel/NF-kappaB transcription factors

    Oncogene

    (1999)
  • N. Kabrun et al.

    The Rel family of proteins in oncogenesis and differentiation

    Semin. Cancer Biol.

    (1994)
  • A.S. Baldwin

    Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB

    J. Clin. Invest.

    (2001)
  • N. Rioux et al.

    The induction of cyclooxygenase-1 by a tobacco carcinogen in U937 human macrophages is correlated to the activation of NF-kappaB

    Carcinogenesis

    (2000)
  • N. Li et al.

    Ionizing radiation and short wavelength UV activate NF-kappaB through two distinct mechanisms

    Proc. Natl. Acad. Sci. USA

    (1998)
  • P.A. Baeuerle et al.

    Phorbol-ester-induced activation of the NF-kappa B transcription factor involves dissociation of an apparently cytoplasmic NF-kappa B/inhibitor complex

    Cold Spring Harb. Symp. Quant. Biol.

    (1988)
  • K. Abeyama et al.

    A role for NF-kappaB-dependent gene transactivation in sunburn

    J. Clin. Invest.

    (2000)
  • M. Wu et al.

    Inhibition of NF-kappaB/Rel induces apoptosis of murine B cells

    EMBO J.

    (1996)
  • A.A. Beg et al.

    An essential role for NF-kappaB in preventing TNF-alpha-induced cell death

    Science

    (1996)
  • Cited by (478)

    • Alkaloids: Their relevance in cancer treatment

      2023, New Insights into Glioblastoma: Diagnosis, Therapeutics and Theranostics
    View all citing articles on Scopus
    View full text