The Nrf2/HO-1 Axis in Cancer Cell Growth and Chemoresistance

Figure 2

Nrf2 activity regulation. In a resting state, Nrf2 is sequestered in the cytoplasm through the binding with Keap1, responsible for Nrf2 ubiquitination and proteasomal degradation via Cul3. Oxidative/electrophilic stress causes a conformational change in Keap1-Cul3, by acting on specific cysteine residues in Keap1, leading to Nrf2 dissociation. Thus, free Nrf2 translocates to the nucleus, which dimerises with small Maf protein and binds to ARE/EpRE sequence within regulatory regions of a wide variety of target genes (e.g., HO-1, GCLC, GCLM, MRPs, and p62). In cancer cells (blue box), Keap1/Nrf2 mutations and Keap1/Cul3 aberrant hypermethylations as well as Keap1 interactions with ETGE motif-containing proteins lead to an increased Nrf2 activation and induction of target genes.