15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a representative J-series
cyclopentenone prostaglandin, exerts cytoprotective effects that are mainly mediated by Nrf2. Nrf2 is a major
transcription factor involved in the transactivation of genes encoding many phase 2 detoxifying and
antioxidant enzymes via interaction with the antioxidant response element (ARE). Recently it has been reported that expression of phase 3 efflux transporters, such as
multidrug resistance-associated proteins (MRPs), is also regulated by Nrf2. It is well known that
cancer cells overexpressing MRPs are more resistant to anticancer drugs. In the present study we have found that 15d-PGJ(2) induces the expression of
MRP1, one of the phase 3 efflux transporters, in human
breast cancer cells (MCF-7). In addition, treatment of MCF-7 cells with 15d-PGJ(2) resulted in nuclear translocation and
DNA binding of Nrf2. In contrast to 15d-PGJ(2), 9,10-dihydro-15d-PGJ(2), an analogue of 15d-PGJ(2) that lacks an electrophilic
cyclopentenone ring moiety, failed to induce not only Nrf2 activation but also
MRP1 upregulation in MCF-7 cells. 15d-PGJ(2)-induced
MRP1 overexpression was abrogated by Nrf2 gene knockdown, using RNA interference. These results, taken together, suggest that 15d-PGJ(2) induces
MRP1 upregulation via Nrf2-ARE signaling.