Chronic inflammation and cancer

Monday, 25/08/2014  |   Cancer  |  no comments

1476-9255-11-23-2-l NF-?B and p53 antagonises each others activity. Various mediators involved in the pathways are indicated. In addition, p53 and NF- ?B can inhibit each other by direct physical interaction through their multimerization domain. Eventually, the effect of activation NF- ?B 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- ?B and p53 indicate activation of these transcription factors. MDM2: mouse double mute 2; ?-TrCP1: beta transducing repeat containing protein1; ARF: alternate reading frame of INK4/ARF locus; ATR: ATM-Rad3 related; CHK: check point kinase; I ?B: inhibitior of kB; IKK: inhibitor of kappaB kinase. Cancer is an extremely complex disease caused by cells that have lost their usual control over growth. The apparent cause of cancer formation may differ case by case, however the basic mechanism is thought to be the following. There are two classes of genes that can control cancer development. Oncogenes and tumor suppressor genes belong to one class, while the other class belongs to the caretaker genes. Healthy cells follow standard rules of growth and proliferation, and have a definitive life span. In contrast, cells with an oncogenic activation undergo much faster cell division with an indefinite life span. Tumor suppressor genes are evolved to inhibit deregulated cell growth. Usually cancer formation ensues when activation and inactivation of an oncogene and a tumor suppressor gene, respectively, occur in a cell at the same time. The caretaker genes control the rate of mutation in the genome. A defective caretaker gene would allow accumulation of mutation in the genome and thus leading to a higher rate of tumor formation. Therefore, cancer formation occurs due to functional defects in multiple genes. Heredity plays important role in cancer formation. However, it appears to be a small causal factor compared to incidence attributed to the modern lifestyle and environment. Smoking, high calorie diet, obesity, alcohol consumption, chronic infection, exposure to radiation and environmental pollutants are considered to be the major risk factors for cancer formation [1]. In fact about 95% cancer can link modern life style and environment with inflammation as the basic underlying cause [2]. An acute inflammatory response is transient, self regulatory and protects our tissues from infection in a healthy cell. The level of pro-inflammatory cytokines that rises to the peak at the height of the response eventually leads to the production of anti-inflammatory cytokines [3]. Thus an acute inflammatory response is faded off to complete the process of healing. In contrast, chronic or persistent tissue inflammation or irritation is correlated with adverse effects and has long been linked with increasing rate of tumor formation by epidemiological studies [4-6]. Cancer promoted by chronic inflammation (called ‘arbuda’) has been cited in Ayurveda, a form of Indian traditional/alternative medicine ˜5000 years ago. Virchow (in 1858) also had observed frequent cancer origination at the site of chronic irritation [4]. Activation of nuclear factor-kappa B (NF- ?B) 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- ?B 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- ?B 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- ?B 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. Pal et al., [5] discuss the role of NF- ?B in chronic inflammation and cancer, highlighting mutual antagonism between NF- ?B 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. NF- ?B, a central regulator of innate immune response, normally is activated in a time dependent manner as a host protection mechanism. It has been now established by numerous independent studies that a persistent long term activation of this factor is tumorigenic and blockade of the activities of an inflammatory mediator regress tumor progression as well as its aggressiveness. Studies from various independent laboratories have already pinpointed some mediators in the NF- ?B activation pathway that undergo aberrant regulation in various cancers. Studies from many laboratories have firmly established a reverse correlation of activation between the NF- ?B and p53 pathways highlighting a prospective avenue in cancer chemotherapy. Several small molecules of natural or synthetic origin many of which target multiple signaling pathways including NF- ?B and p53 apparently hold a great promise to move the cancer treatment and management in the desired direction. In this direction, various potential pharmacological agents have been isolated that activate p53 in tumor cells with high potency at very low concentration. Most of these small molecules appears to have at least part their mode action through inhibition of NF- ?B. Conversely, it is conceivable that the anticancer activity of many NF- ?B inhibitors is partly due to their ability to induce p53 in cancer cells. Efforts are already underway to find small molecules that will with higher specificity rectify the defect in the pathways to suppress NF- ?B activity. Clearly, more studies are needed to provide us with more insightful understanding of the mechanism of deregulation and the underlying cause. Given the role of NF- ?B in innate immunity and cancer, a desired objective would be to achieve the ability to turn off and on the function of NF- ?B with high precision and as needed. References 1. Stein CJ, Colditz GA: Modifiable risk factors for cancer. Br J Cancer 2004, 90:299-303. 2. 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. 3. Rossi AG, Sawatzky DA: The Resolution of Inflammation. Birkhauser: Basel; 2008. 4. Balkwill F, Mantovani A: Inflammation and cancer: back to Virchow? Lancet 2001, 357:539-545. 5. Pal S, Bhattacharjee A, Ali A, et al. Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism. Journal of Inflammation. 2014, 11:23 doi:10.1186/1476-9255-11-23 http://www.journal-inflammation.com/content/11/1/23

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