Inhibition of NRF2 in cancer cells enhances apoptotic response and suppresses cell growth:a potential involvement of the p53 signaling

Abstract

The integrated regulation of oxidative stress‐response transcription factors could be critical for animals to promote the survival of normal cells and to facilitate the removal of abnormal cells with inherited genetic damage. In the current study, we have investigated the effect of NRF2, a cell survival‐promoting factor, on the p53 signaling. In NRF2 inhibited ovarian cancer cells, the growth arrest in G0/G1 phase and the loss of tumorigenecity in mice were accompanied by the increase in p53 transcription activity as well as its target gene expression such as p21 and Gadd45a. In NRF2‐deleted murine embryonic fibroblasts (MEFs), the accumulation of p53 protein together with the suppression of murine double minute 2 (MDM2) expression was observed although accumulated p53 protein might not be functional. Our further promoter analysis showed that NRF2 can be involved in the regulation of basal expression of MDM2 through the proximal ARE in its promoter. Collectively, our results suggest that a novel evidence that the inhibition of NRF2 may stimulate the p53 signaling, which can result in cell growth limitation and facilitation of apoptotic response upon oxidative stress.