The yin and yang of nrf2-regulated selenoproteins in carcinogenesis

Abstract

The NF-E2-related factor-2 (Nrf2) is a transcription factor which regulates the major cellular defense systems and thereby contributes to the prevention of many diseases including cancer. Selenium deficiency is associated with a higher cancer risk making also this essential trace element a promising candidate for cancer prevention. Two selenoproteins, thioredoxin reductase-1 (TrxR1) and glutathione peroxidase-2 (GPx2), are targets for Nrf2. Selenium deficiency activates Nrf2 as does a TrxR1 knockout making a synergism between both systems plausible. Although this might hold true for healthy cells, the interplay may turn into the opposite in cancer cells. The induction of the detoxifying and antioxidant enzymes by Nrf2 will make cancer cells chemoresistant and will protect them against oxidative damage. The essential role of TrxR1 in maintaining proliferation makes its upregulation in cancer cells detrimental. The anti-inflammatory potential of GPx2 will help to inhibit cancer initiation and inflammation-triggered promotion, but its growth supporting potential will also support tumor growth. This paper considers beneficial and adverse consequences of the activation of Nrf2 and the selenoproteins which appear to depend on the cancer stage.

Figure 1

Interplay between Nrf2 and the selenoproteins thioredoxin reductase-1 (TrxR1) and glutathione peroxidase-2 (GPx2). (a) In the presence of selenium, the activation of Nrf2 leads to increased mRNA of both enzymes which can be translated into respective proteins. (b) Under selenium deficiency, Nrf2 is activated which in principle can lead to an induction of TrxR1 and GPx2 mRNA. Due to lack of selenium, the proteins cannot be synthesized. Decrease in TrxR1 further activates Nrf2, which subsequently upregulates enzymes of the glutathione (GSH) system. These, in part at least, can compensate the reduced TrxR1 activity. For details see text.