NRF2, cancer and calorie restriction

Abstract

The transcription factor NF-E2-related factor (NRF2) is a key regulator of several enzymatic pathways, including cytoprotective enzymes in highly metabolic organs. In this review, we summarize the ongoing research related to NRF2 activity in cancer development, focusing on in vivo studies using NRF2 knockout (KO) mice, which have helped in defining the crucial role of NRF2 in chemoprevention. The lower cancer protection observed in NRF2 KO mice under calorie restriction (CR) suggests that most of the beneficial effects of CR on the carcinogenesis process are likely mediated by NRF2. We propose that future interventions in cancer treatment would be carried out through the activation of NRF2 in somatic cells, which will lead to a delay or prevention of the onset of some forms of human cancers, and subsequently an extension of health- and lifespan.

Figure 1

Diagram of the activation of NRF2. Calorie restriction and a number of phytochemicals are able to induce the release of NRF2 from Keap1, allowing it to enter into the nucleus. Once in the nucleus, NRF2 binds to ARE sequences in the promoter of antioxidant and detoxifying enzymes, inducing their expression. Increased levels of these NRF2 downstream targets prevent age-related increases in cancer and ameliorates other age-related diseases, leading to an improved quality of life.