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.

Comparison of the seleno-transcriptome expression between human non-cancerous mammary epithelial cells and two human breast cancer cell lines

“…GPX2 is required in healthy tissues to maintain normal self-renewing of the gastrointestinal epithelium and to reduce inflammatory processes. Therefore, GPX2 should inhibit carcinogenesis; however, once a cell has been programmed to proliferate in an uncontrolled way, GPX2 supports the growth of cells by inhibiting apoptosis (39). This appears to be consistent with the present results.…”

Selenoproteins: Molecular Pathways and Physiological Roles

“…GPx2 is preferentially expressed in the gastrointestinal epithelium, but its elevated expression was also found in epitheliumderived tumors. However, whether GPx2 has a protective role against cancer and/or promotes cancer development still remains an open question (30). One line of evidence supporting a cancer preventive role of GPx2 comes from the finding that GPx2 gene expression is under control of the antioxidant response transcription factor Nrf2.…”

“…These enzymes, and TR1 itself, are targets of the Nrf2 transcription factor. Therefore, induction of Nrf2-dependent antioxidant responses may protect cancer cells from oxidative stress (30,284). However, additional studies will be needed to elucidate interdependencies of different redox systems in the context of normal tissues and during tumor development.…”

Selective Up-regulation of Human Selenoproteins in Response to Oxidative Stress

“…Their targets include a multitude of genes involved in the stress response, antioxidant activity, the anti-inflammatory response, DNA repair, molecular chaperones, proteasome systems, and two selenoproteins, Gpx2 (mostly expressed in the intestine) and TR1 (an essential cytoplasmic enzyme). The degree of expression of these genes involves other transcription factors (30,31). A link between selenium, selenoprotein expression, and the antioxidant response has been established via NRF2, which is induced in certain cell lines during severe selenium deficiency or complete loss of selenoproteins obtained by tRNA Sec gene inactivation (32).…”