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Review
. 2014 Aug 9:11:23.
doi: 10.1186/1476-9255-11-23. eCollection 2014.

Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism

Srabani Pal #  1 , Ashish Bhattacharjee #  2 , Asif Ali  3 , Narayan C Mandal  4 , Subhash C Mandal  1 , Mahadeb Pal  3
Affiliations
Review

Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism

Srabani Pal et al. J Inflamm (Lond). .

Abstract

Activation of nuclear factor-kappa B (NF- κB) as a mechanism of host defense against infection and stress is the central mediator of inflammatory responses. A normal (acute) inflammatory response is activated on urgent basis and is auto-regulated. Chronic inflammation that results due to failure in the regulatory mechanism, however, is largely considered as a critical determinant in the initiation and progression of various forms of cancer. Mechanistically, NF- κB favors this process by inducing various genes responsible for cell survival, proliferation, migration, invasion while at the same time antagonizing growth regulators including tumor suppressor p53. It has been shown by various independent investigations that a down regulation of NF- κB activity directly, or indirectly through the activation of the p53 pathway reduces tumor growth substantially. Therefore, there is a huge effort driven by many laboratories to understand the NF- κB signaling pathways to intervene the function of this crucial player in inflammation and tumorigenesis in order to find an effective inhibitor directly, or through the p53 tumor suppressor. We discuss here on the role of NF- κB in chronic inflammation and cancer, highlighting mutual antagonism between NF- κB and p53 pathways in the process. We also discuss prospective pharmacological modulators of these two pathways, including those that were already tested to affect this mutual antagonism.

Keywords: Cancer; Chemoprevention; Inflammation; Inhibitor of kB (I κB); Inhibitor of kappaB kinase (IKK); Lipopolysachharides (LPS); MDM2; Nuclear factor kappa B (NF- κB); Phytochemicals; Small molecule inhibitors; Toll like receptor (TLR); Tumor necrosis factor (TNF); Tumor suppressor p53 (TP53).

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Figures

Figure 1
Figure 1
Activation of NF-κB signaling through canonical and alternative pathways. Different cytokines and pathogen associated molecules (PAMs) interact with their specific receptors (cytokine receptors:TNF receptor, IL1 receptor; PAMs recognize TLRs present on outer cell membrane (TLR1,-2,-4,-5,-6, and -10) or on the endosomal membrane (TLR3, -7, -8 and -9) in the initial stage of NF- κB activation pathway. The activated receptor recruit the adapter components (not shown) such as Myd88 and TRIF (TIR domain-containing adaptor inducing IFN- γ, except TLR3 which utilizes TRIF without Myd88 (Myeloid differentiation primary response protein 88) to transmit the signal through activation of several mediators components including IRAK4 (IL1 receptor associated kinase 4), TRAF6 (TNF receptor associated factor 6), to activate IKKK i.e., MEKK1 (mitogen activated protein (MAP) kinase/extracellular signa l regulated kinase (ERK) kinase kinase 1), MEKK3 and TAK1 (transforming growth factor β activated kinase) to act to phosphorylate IKK complex. The activated IKK modifies the inhibitor I κB for its proteasomal degradation. NF- κB is released free to enter into the nucleus for transcriptional activation of the target genes. The canonical pathway is active in innate immunity, inflammation and cell survival; the alternative pathway mediates the humoral immunity.
Figure 2
Figure 2
NF-κB and p53 antagonises each others activity. Various mediators involved in the pathways are indicated. In addition, p53 and NF- κB can inhibit each other by direct physical interaction through their multimerization domain. Eventually, the effect of activation NF- κB pathway prevents the activation of p53 pathway and vice versa. The detail is described in the text. The black colored upward arrows adjacent to NF- κB and p53 indicate activation of these transcription factors. MDM2: mouse double mute 2; β-TrCP1: beta transducing repeat containing protein1; ARF: alternate reading frame of INK4/ARF locus; ATR: ATM-Rad3 related; CHK: check point kinase; I κB: inhibitior of kB; IKK: inhibitor of kappaB kinase.
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References

    1. Stein CJ, Colditz GA. Modifiable risk factors for cancer. Br J Cancer. 2004;90:299–303. - PMC - PubMed
    1. Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB. Cancer is a preventable disease that requires major lifestyle changes. Pharm Res. 2008;25:2097–2116. - PMC - PubMed
    1. Rossi AG, Sawatzky DA. The Resolution of Inflammation. Birkhauser: Basel; 2008.
    1. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–545. - PubMed
    1. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–867. - PMC - PubMed
-