Figure 4.

Nrf2 in normal (left) and cancer (right) cells. In normal cells, Nrf2 signaling is highly upregulated, with Nrf2 being mainly activated for cell protection. Under this regulated environment, Nrf2 fights the intracellular ROS inadvertently produced during aerobic metabolism by promoting the gene expressions of different antioxidants. The antioxidant response is vital for detoxifying cells with toxic ROS levels, avoiding distress conditions where ROS-induced mutagenic events can occur. Apart from that, the fine balance of ROS by antioxidants allows for a synchronized and self-controlled eustress state, where prooxidants and antioxidants work in harmony to regulate the intensity and duration of redox signaling. Thus, under normal conditions, the antioxidant response controlled by Nrf2 is key in cancer prevention. However, many cancer cells have constitutive and dysregulated activation of Nrf2. In this scenario, higher Nrf2 levels combat intracellular ROS of anaerobic metabolism due to the Warburg effect. In addition, in many cancer cells with Nrf2 upregulation, Nrf2 has been implicated in the activation of drug efflux transporters, having, in general, a major role in cell cancer cell detoxification. Additionally, cancer cells take advantage of the antioxidant role of Nrf2 to keep ROS at minimum levels by transiting to a stem state. Stemness, antioxidants, and efflux transporters confer great resistance to the main therapies currently practiced in the fight against cancer, namely chemo- and radiotherapy. Hence, in cancer cells, Nrf2 signaling is vital for tumor survival after treatment and its subsequent repopulation due to Nrf2-induced stemness properties.