Novel NF-Kb links inflammation and cancer promotion

A recent paper by researchers at the University of California [1] reveals a novel mechanism by which chronic inflammation may play a decisive role in the promotion of cancer. This mechanism is a sort of molecular “cross-talk” between two processes in cells which were thought to be distinct – cell development and inflammation. This cross-talk comes through the actions of a protein, p100, which has been found to be crucial in a cell’s normal developmental metabolic pathways as well as in the cell’s response to inflammation. Novel cancer therapeutic treatments which target developmental pathways linked to chronic inflammation via p100 may prove effective in conjunction with the use of current anti-inflammatories such as NSAIDS.

NF-κB activity is inducible by a diverse range of stimuli including pathogen derived substances and intercellular mediators of inflammation. It is known that NF-κB is normally repressed by three different intracellular inhibitors (IκB-a,b,e proteins),and that during classical inflammatory signaling these inhibitors are released from binding NF-κB, resulting in its activation. A second, independent NF-κB activation pathway is thought to be activated in response to cell developmental signals rather than inflammatory signals. The molecular mechanism of this particular pathway has remained uncertain, but the results of this study show that a fourth IκB inhibitor (p100) is involved in the activation of NF-κB in developmental pathway signaling, such as during lymphoid organogenesis (see included figure).

This diagram reveals the cross-talk between NF-κB activation via inflammatory or developmental signaling – inflammatory signaling can activate developmental (cell reproduction and differentiation) pathways to some extent and vice-verse. And further work by the researchers showed that the “cross-activation” of developmental pathways by classical inflammatory signaling was much stronger, and of longer duration, than the normal developmental activation signal strength. For example, a 1 hr pulse of TNF-a stimulation resulted in an elevation of p100 protein of about 4-fold, that persisted for more than 20 hr. Remarkably, the researchers also showed that the strength of this cross-talk increased with repeated signaling – in other words, the longer cells were exposed to inflammatory signals via TNF-a, the more they were stimulated to reproduce! This is in marked contrast to the normally accepted role of TNF-a in signaling cell death.

The researchers speculate that in epithelial cells that are exposed to prolonged periods of inflammation, such as they might experience during chronic inflammatory diseases, the amount of cross-talk between the classic TNF-a mediated inflammatory cell death pathway and the p100 mediated developmental cell growth pathway may profoundly shift, with the inflammatory signals generating a stronger and stronger cell growth signal in place of the expected cell death signal. This could be the mechanism responsible for chronic inflammations being able to promote the growth of many types of cancers – after prolonged exposure, inflammatory TNF-a signals that were originally responsible for inducing cell death (and resolving inflammation and tissue repair processes) become instead growth stimulating signals that drive epithelial cells toward unrestrained cancerous growth.


1. Basak S, Kim H, Kearns JD, Tergaonkar V, O'Dea E, Werner SL, Benedict CA, Ware CF, Ghosh G, Verma IM, Hoffmann A.(2007) A fourth IkappaB protein within the NF-kappaB signaling module. Cell. Vol 128(2) p369-81.