Numerous observations indicate a strong link between chronic inflammation and cancer. This link is supported by substantial experimental evidence indicating mutual negative regulation of NF-κB, the major regulator of inflammation, and p53, the major tumor suppressor. This antagonistic relationship reflects the opposite principles of the physiological responses driven by these transcription factors, which act as sensors and mediators of intrinsic and extrinsic cell stresses, respectively. Constitutive activation of NF-κB, the underlying cause of chronic inflammation, is a common acquired characteristic of tumors. A variety of experimental methods have been used to demonstrate that constitutive activation of NF-κB reduces the tumor suppressor activity of p53, thereby creating permissive conditions for dominant oncogene-mediated transformation. Loss of p53 activity is also a characteristic of the majority of tumors and results in unleashed inflammatory responses due to loss of p53-mediated NF-κB suppression. On the other hand, in natural or pharmacological situations of enforced p53 activation, NF-κB activity, inflammation, and immune responses are reduced, resulting in different pathologies. It is likely that the chronic inflammation that is commonly acquired in various tissues of older mammals leads to general suppression of p53 function, which would explain the increased risk of cancer observed in aging animals and humans. Although the molecular mechanisms underlying reciprocal negative regulation of p53 and NF-κB remain to be deciphered, this phenomenon has important implications for pharmacological prevention of cancer and aging and for new approaches to control inflammation.
Keywords: NF-κB; aging; apoptosis; cancer; chemokines; cytokines; immune response; infection; senescence.