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The International Journal of Biochemistry & Cell Biology 42 (2010) 1061–1065

Contents lists available at ScienceDirect

The International Journal of Biochemistry& Cell Biology

 j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b i o c e l

Medicine in focus

Colon carcinogenesis: Learning from NF-B and AP-1

Aristides G. Vaiopoulos, Katerina K. Papachroni, Athanasios G. Papavassiliou ∗

Department of Biological Chemistry, University of Athens Medical School, 75 Mikras Asias Street, Goudi, 11527 Athens, Greece

a r t i c l e i n f o

 Article history:

Received 28 January 2010

Received in revised form 15 March 2010

Accepted 22 March 2010

Available online 27 March 2010

Keywords:

Colorectal cancer

Inflammation

Signal transduction

NF-B

AP-1

a b s t r a c t

Colorectal cancer (CRC) is among the most common types of cancer attributed to genetic alterations. Its

manifestation implicates NF-B and AP-1 signaling pathways by virtue of their regulative role on the

genetic control of cell cycle and apoptosis as well as by their capacity to be constitutively activated or

exogenously induced by growth factors, cytokines, stress signals and oncoproteins. In CRC, the positiveimpactof NF-B andAP-1on thetranscriptionof angiogenicand invasivefactors strongly implicates these

transcriptionfactorsin the transitionof benign carcinomastowards a metastaticphenotype.Furthermore,

thederegulatedfunctionof NF-B andAP-1 in CRCcellsaffects inflammatory cascades, manifestedby the

ample production of inflammatory mediators. In thisperspective,inhibitionof NF-B and AP-1signaling

mechanisms has become a rational target in the development of novel therapeutic approaches against

CRC.

© 2010 Elsevier Ltd. All rights reserved.

1. Introduction

Colorectal cancer (CRC) is a leading cause of morbidity and

mortality. It is presented as a multistep ‘genetic’ disorder, the

development and progression of which are caused by characterised

mutations andabnormalities in signal transductionpathways. Most

cases of sporadic and familial CRC are associated with mutations

in the molecules along the Wnt signaling pathway, which lead

to aberrant ␤-catenin activation and deregulated gene transcrip-

tion. The development and progression of CRC, however, requires

the concurrent failure of other protective mechanisms, includ-

ing the p53 tumour suppressor gene, the pro-apoptotic protein

Bcl-2-associated X protein (BAX), the anti-proliferative protein

transforming growth factor beta (TGF-␤) or its downstream tran-

scription factors, the SMAD proteins, as well as induction of 

oncogene pathways (Markowitz and Bertagnolli, 2009). Recently,

the transcription factors nuclear factor-B (NF-B) and activator

protein-1 (AP-1), which have an established role in the regulation

of cell cycle and the progression of immune-mediated and inflam-matory diseases, have been implicated in the tumourigenesis of 

colon epithelium.

∗ Corresponding author. Tel.: +30 210 7462 508/9; fax: +30 210 7791 207.

E-mail addresses: papavas@med.uoa.gr, gpapavas@ath.forthnet.gr

(A.G. Papavassiliou).

2. Pathogenesis

 2.1. The role of NF-ÄB in CRC 

NF-B, collectively referring to homo- and heterodimeric com-

plexes of members of five protein families [(RelA, RelB, c-Rel,

p50/p105 (NF-B1), p52/p100 (NF-B2)] (Basseres and Baldwin,

2006). All NF-B members share a 300-aa Rel-homology domain

responsible for DNA binding, dimerization and interaction with

their inhibitors IB’s (Shen and Tergaonkar, 2009). Upon receipt

of a signal[cytokines, growthfactors (GFs),stress signals, oncopro-

teins], IB’s are phosphorylated and proteolyticaly removed and

NF-B enters the nucleus to regulate genes involved in cell cycle,

cell survival and innate and adaptive immune responses (Basseres

and Baldwin, 2006). Evidence for involvement of NF-B or IB

members in oncogenesis is based on several observations, namely

that (i) NF-B proteins are members of a proto-oncogene family;

(ii) the NF-ÄB2 ( p52/ p100) geneandthe Bcl-3 gene are translocated

in certain lymphomas; (iii) NF-ÄB gene is activated by viral trans-forming proteins; (iv) loss of  NF-ÄB1 ( p50/ p105) accelerates B-cell

growth and turnover in vivo and (v) exposure of cells to IB anti-

sense results in oncogenic transformation (Basseres and Baldwin,

2006).

In CRC, activation of the noncanonical NF-B1 pathway in

response to␤-cateninsignaling is reported (Lauscheret al.,2010) as

well as activation of distinct NF-B complexes (p50/p50, RelA/p52)

upon release of endogenous ceramide, a bioactive lipid implicated

in colon cancer (Colell et al., 2002). Activation of NF-B promotes

tumour invasiveness and links the inflammatory processes to car-

cinogenesis (Horst et al., 2009).

1357-2725/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.

doi:10.1016/j.biocel.2010.03.018

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In colitis-associated intestinal cancer (CAC) correlations have

been made with Ras and p53-activated pathways (Karin, 2006;

Basseres and Baldwin, 2006). NF-B induces cell proliferation

by potentiating the phosphoinositide 3-kinase (PI3-K)-AKT-

mammalian target of rapamycin (mTOR) signaling pathway and

the key cell-cycle regulatory genes including cyclin D1, c-myc ,

cyclin-dependent kinases (CDKs) (Shen and Tergaonkar, 2009). In

CRC, NF-B suppresses apoptosis by inducing genes encoding anti-

oxidant enzymes and by inhibiting the c-Jun N-terminal kinase

(JNK) cascade (Bubici et al., 2006). In human colon cancer cell

lines, curcumin, the principal substanceof the spice turmeric, inter-

acts with the NF-B-reactive oxygen species (ROS)–JNK pathway

and induces apoptosis in vitro (Collett and Campbell, 2004). NF-B

also mediates the enhanced angiogenesis and invasiveness of CRC

tumour cells, by up-regulating vascular endothelial growth factor

(VEGF), cyclooxygenase 2 (COX-2), interleukine (IL)-6, cell adhe-

sion molecules (ICAM-1, VCAM-1) and matrix metalloproteinases

(MMPs), that collectively facilitate progression to a metastatic

phenotype (Basseres and Baldwin, 2006; Chen and Castranova,

2007). Furthermore, NF-B confers anti-apoptotic advantage to

CRC tumour cells via induction of the anti-apoptotic genes Bcl-2,

Bcl-x and cIAPs (Chenand Castranova, 2007). Inaccord to thesedata,

analysis of human CRC tissue revealed constitutive up-regulation

of RelA, correlated with the expression of Bcl-2 and Bcl-x (Yu etal.,2004).

However, while NF-B has emerged as a critical promoter of 

inflammation-linked cancers, strong evidence also suggests that

it suppresses chemically induced skin and liver cancers, by inhi-

bition of cell-cycle progression or down-regulation of JNK activity

(Karin, 2006; Chenand Castranova, 2007). Nevertheless, evenwhen

NF-B suppresses tumourigenesis, its inflammatory activity pro-

motes tumour development by the induction of pro-inflammatory

cytokines, tumour necrosis factor alpha (TNF-␣) and IL-6, which

serve as GFs for premalignant cells as well as for already formed

tumours (Karin, 2006).

 2.2. The role of AP-1 in CRC 

TheAP-1groupoftranscriptionfactorsconsistsofdimersmainly

of the Jun (c-Jun, JunB, JunD) and Fos (c-Fos, FosB, Fra-1, Fra-2)

subfamilies that harbor a basic leucine zipper (bZIP) domain and

can form duplexes between themselves and with other bZIP pro-

teins. This advantage for complex formation allows AP-1 to target

a broad range of DNA-binding sites and regulate genes engaged in

cell cycle (cyclin D1, p53, p21, p19, p16) and inflammation (cox-2).

AP-1 contributes to basal gene expression but also participates in

the immediate-early cellular response to a wide gamut of physio-

logical and pathological stimuli, including, GFs, pro-inflammatory

cytokines, stress signals, infections and most importantly, onco-

genic signals. AP-1 activation is induced by cis-elements in the

promoters of AP-1-encoding genes, followed by rapid phosphory-

lation of the AP-1 proteins mainly through the mitogen-activatedprotein kinase (MAPK) cascade. GFs activate extracellular signal-

regulated kinase (ERK), pro-inflammatory cytokines and genotoxic

stress induce p38 MAPKs and JNKs, while oncoproteins (e.g. Src,

Ras) induce the ERK or JNK pathway (see Fig. 2) (Karamouzis et al.,

2007; Shaulian and Karin, 2001, 2002).

Recently, enhanced activity of AP-1 in human colon adeno-

carcinoma grade II cell line has been demonstrated (Yao et al.,

1994), where AP-1 contributes to transcriptional induction of 

redox-regulating enzymes in the areas of solid tumours. Immuno-

histochemical analysis on human colon adenocarcinoma revealed

that AP-1 is expressed in the stromal myofibroblasts surrounding

the tumour in the majority of cases examined, and this expression

correlates positively with the expression of VEGF, a downstream

target of AP-1, epidermal growth factor receptor (EGFR) and COX-

2 (Konstantinopoulos et al., 2007a). In addition, data from studies

on experimental models and examination of human tissue of CRC

suggests that the presence of high concentrations of bile acids

induces AP-1 expression, perhaps through protein kinase C (PKC)

and ERK signaling, and results in COX-2 stimulation that medi-

ates anti-apoptosis, motility and invasion (Debruyne et al., 2001).

Dataconcerning a seriesof signalingcascades in CRC epithelialcells

mediated by or resultingin AP-1 activity have been reported.These

include activation of the Wnt/␤-catenin pathway which regulates

c-jun and fra-1 genes (Mann et al., 1999), and also the Ras-GTPases

cascades. Gain-of-function mutations in the K-ras gene stimulate

the ERK and JNK pathway, potentiate AP-1 and have been docu-

mented to be crucial for the development of CRC ( Ashida et al.,

2005).

Interestingly, AP-1 is likely to act as a homeostasis switch regu-

latingthe cell cycle. Dependingon the duration andtype of stimuli,

AP-1 up-regulates cyclin D1 but can also act as an anti-apoptotic

factor via negative modulation of p53 (Shaulian and Karin, 2001)

and induction of the anti-apoptotic Bcl genes (Bcl-3, Bim). More-

over, dependingon thestimulus(e.g. sustainedJNK activation)AP-1

may encourage cell death by up-regulating Fas ligand (FasL) and

thus promote apoptosis. Notably, AP-1 in human colon cancer cell

lines mediates an anti-apoptotic response to the hypoxic condi-

tions often encountered in the environment of solid tumours andthus contributes to chemo- and radiotherapy resistance (Shaulian

and Karin, 2002). Similar to NF-B, AP-1 also controls the expres-

sion of angiogenic (VEGF) (Grau et al., 2006) and invasive factors

(MMPs) of the cancer cells (Debruyne et al., 2001).

 2.3. NF-ÄB and AP-1: an intriguing link between cancer and

inflammation

Chronic inflammation has been correlated with carcinogenesis

in a number of human malignancies. The production of ROS, the

epigenetic changes and the release of cytokines atthe site ofinflam-

mation are events with documented carcinogenic capacity that

create a vicious circuitry between the two processes (Fig. 1). This

relationship has been particularly studied in malignancies of thegastrointestinal tract, where the risk of carcinogenesis increases in

the presence of chronic inflammation-inducing conditions (Maeda

andOmata, 2008). Emphasis is given on the role of NF-B and AP-1

as mediators of the cross-talk between inflammation and cancer,

given their induction by inflammatory cytokines (TNF-␣, IL-1␤, IL-

6, IL-8), the presence of regulatory elements for NF-B and AP-1

in the promoters of inflammatory genes (cox-2, MMPs) and their

known impact on cell proliferation.

COX-2 expression is strongly correlated to intestinal tumouri-

genesis, as shown by the studies on animal models and humans.

CAC is more frequent in patients with inflammatory bowel disease

(IBD) and epidemiologic studies show a reductionin CRC incidence

among chronic users of non-steroidal anti-inflammatory drugs

(NSAIDs) (Sinicrope and Gill, 2004). In a murine model of familialadenomatous polyposis (FAP), deletion of the murine cox-2 gene in

polyps-pronemice( Apc 716),wasfoundtodramaticallyreducethe

number of intestinal polyps in double knockoutmice relativeto cox-

 2 wild-type animals (Oshima et al., 1996). Furthermore, in genetic

or carcinogen-induced colon cancer modelsystems, treatmentwith

traditional NSAIDs or selective COX-2 inhibitors reduces tumour

size and multiplicity.The relevanceof these findings to human neo-

plasia was shown in patients with germline APC mutations and the

FAP syndrome, where treatment with NSAID effectively regressed

colorectal adenomas relative to placebo (Sinicrope and Gill, 2004).

The promoter of  cox-2 harbors binding sites for both AP-1

and NF-B (Konstantinopoulos et al., 2007b). Experimental data

from animal models show that reduced activation of NF-B dimin-

ishes the risk of malignant transformation. In CAC animal model,

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Fig. 1. The vicious circuitry of inflammation and cancer. Growth factors (GFs) and cytokines mediate the cross-talk between inflammatory cells and myofibroblasts by

inducing NF-B and AP-1-mediated expression of angiogenic, invasive and inflammatory mediators. These in turn act on the epithelial tumour cells and stimulate activation

of MAPK cascades resulting in transcriptional activation of genes involved in proliferation and metastasis. Moreover, tumour cells produce IL-8 and necrotic by-products

which favor a hypoxic environment. These events further potentiate NF-B in inflammatory cells and trigger production of cytokines, COX-2, VEGF and MMPs. Tumour cells

also mediate fibroblast transformationto myofibroblastsby secretionof TGF-␤, and myofibroblasts consecutively induce NF-B- andAP-1-mediated expression of VEGF and

COX-2. Based on data from Vandoros et al. (2006), Konstantinopoulos et al. (2007a), Maeda and Omata (2008) and Sanchez-Munoz et al. (2008).

conditional inactivation of  IKK ̌ gene, a signaling intermediate of 

NF-B pathway, revealed that the IKK␤-mediated NF-B activa-

tion contributes to CAC through two distinct cell-type specific

mechanisms. In enterocytes it activates anti-apoptotic genes and

thereby suppressesthe apoptoticeliminationof preneoplasticcells,

whereas in myeloid cells it promotes production of cytokines that

serve as GFs for premalignant enterocytes (Karin, 2006). Studies in

the same system revealed that any single AP-1 protein is dispens-

able for CAC and perhaps several AP-1 proteins have to be targeted

to impair carcinogenesis (Hasselblatt et al., 2008).

In CRC, NF-B is activated both in the tumour cells and in

the cells of the surrounding inflammatory stroma (Grau et al.,

2006; Karin, 2006; Konstantinopoulos et al., 2007a). Stromal cellsgenerate oncogenic signals which favour remodeling towards a

malignant phenotype of fibroblasts, namely the myofibroblasts

(Konstantinopoulos et al., 2007a). Inflammatory cells and myofi-

broblasts that congregate at tumour sites secret a variety of GFs

and cytokines that enhance tumour cell proliferation and inva-

sion. NF-B released by the tumour cells potentiates the secretion

of VEGF, IL-8 and MMPs from the inflammatory cells and acts

in concert with AP-1 to regulate expression of VEGF by the

stromal myofibroblasts (Fig. 1). Expression of COX-2 in the CRC

cells further stimulates pro-angiogenic prostaglandin release and

expression of MMP-2 (Debruyne et al., 2001). Increased expres-

sion of COX-2 in both epithelial and stromal cells correlates with

EGFR expression, c-Jun/AP-1 and NF-B activation. Moreover, per-

oxisome proliferator-activated receptor gamma (PPAR ␥), a nuclear

receptor which inhibits the action of both AP-1 and NF-B, acts as

an on/off switch for the production of COX-2. It is down-regulated

in CRC tissue permitting the unopposed AP-1/NF-B transcrip-

tional activity and up-regulation of their downstream target COX-2

(Konstantinopoulos et al., 2007a,b; Vandoros et al., 2006).

3. Therapy 

The plethora of experimental data supports the notion that

NF-B and AP-1 exert a fundamental role in growth and pro-

gression of CRC and encourages the endeavor to employ them as

rational targets for the development of novel therapeutic strate-

gies. Indeed, more than 700 compounds, in the form of smallmolecules from natural/dietary sources (nutraceuticals), synthetic

compounds and cell permeable peptides, reported to inhibit vari-

ous steps of NF-B activation have entered preclinical and clinical

trials (Shen and Tergaonkar, 2009). Antisense RNA and gene ther-

apy (achieving over-expression of IB) capable of blocking IB

kinase (IKK) and IKK upstream signaling, IB degradation and

nuclear function of NF-B, are also tested (Sethi and Tergaonkar,

2009; Shen and Tergaonkar, 2009) (Fig. 2). Efforts have also been

made towards use of already known natural agents with potent

anti-AP-1 effect as well as towards the development of AP-1 novel

signaling pathway inhibitors (Ashida et al., 2005) (Fig. 2). More-

over, NF-B and AP-1 being at the convergence point of several

epithelial-to-mesenchymal transition (EMT) pathways, along with

the AKT/mTOR axis, MAPK, ␤-catenin and PKC, present valuable

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Fig. 2. NF-B and AP-1 pathways as putative targets for therapeutic intervention. NF-B inhibition on various levels of the signaling cascades involves the following: (i) IKK

and IKK upstream signaling inhibitors, comprising small natural and synthesized molecules (e.g. curcumin), receptor blockers (e.g. anti-TNF); (ii) IB degradation inhibitors,

including proteasomeinhibitors; and (iii)NF-B nuclear translocation/DNA-binding inhibitors, including cell permeablepeptides, antisenseRNA. AP-1inhibitors may target:

(i) receptor components, e.g. anti-EGFR; (ii) constituents of the MAPK signaling cascade; (iii) AP-1 dimerisation; (iv) AP-1 DNA binding; and (v) AP-1 interaction with

transcriptional co-factors. PPAR ␥ ligands [e.g. non-steroidal anti-inflammatory drugs (NSAIDs), thiazolidinediones] impair COX-2 and VEGF production by blocking NF-B

and AP-1 activity.

targets to control EMT and the progression of human epithelial

cancers, including CRC. Several inhibitors targeting these signal-

ing cascades as well as upstream EMT signaling pathways induced

by receptor and nonreceptor tyrosine kinases [e.g. EGFR, IGF-R,

VEGF-R, integrins/focal adhesion kinase (FAK), Src] and G-protein-

coupled receptors (GPCR) are tested in preclinical and clinical trials

or are currently used in the clinic for cancer treatment (Sabbah et

al., 2008). The formulation of targeted therapy without severe side-

effects such as systemic toxicity or broad immunosuppression will

provide additional weapons in the therapeutic arsenal against CRC.

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