Cadmium is one of the most abundant environment pollutants, and has been widely recognized as a human carcinogen. Nrf2 is a key transcription factor responsible for the induction of a group of enzymes that detoxify various oxidants and chemical carcinogens. Previous studies showed that exposure of cells to cadmium increased Nrf2 protein level presumably by inhibition of ubiquitin/proteasome-mediated Nrf2 degradation. Here we report that such an effect of cadmium on Nrf2 expression is strongly time-dependent and long-term exposure to cadmium may impair Nrf2-mediated defense system. Induction of Nrf2 protein by cadmium (1-15 μM) can be detected as early as 30 min following treatment, and remains elevated for several hours. The induced Nrf2 protein level then begins to decrease and backs to basal level by 12 h. This time-dependent effect was not seen with other Nrf2 inducers such as sulforaphane, tert-butyl hydroquinone, and proteasome inhibitor MG-132, which induce sustained elevation of Nrf2 protein. More importantly, a decline in Nrf2 induction as observed after cadmium exposure for 12 h prevents further Nrf2 activation by chemical inducers. To better understand this inhibitory mechanism, we examined time-dependent effects of cadmium exposure on Nrf2 expression at different regulation levels. Both short-term (less than 4 h) and long-term (more than 12 h) cadmium exposures show similar potency to block Nrf2 protein degradation, and are able to inhibit Nrf2 ubiquitination through both Keap1-dependent and independent mechanisms. In contrast, long-term exposure to cadmium significantly reduces Nrf2 mRNA level, and also impairs Nrf2 translation. Thus, we conclude that downregulation of Nrf2 transcription and translation may counteract its inhibitory effect on Nrf2 protein degradation, and lead to the impairment of Nrf2 induction as seen after long-term exposure to cadmium.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA