Multidrug resistance-associated protein 1 mediates 15-deoxy-Δ(12,14)-prostaglandin J2-induced expression of glutamate cysteine ligase expression via Nrf2 signaling in human breast cancer cells.

15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a representative J-series cyclopentenone prostaglandin bearing an electrophilic α,β-unsaturated carbonyl group. In the present study, treatment of human breast cancer MCF-7 cells with 15d-PGJ2 caused the up-regulation of the glutamate cysteine ligase catalytic (GCLC) subunit, the rate-limiting enzyme in glutathione (GSH) synthesis. 15d-PGJ2 treatment caused nuclear translocation and transactivation of Nrf2, a redox-sensitive transcription factor responsible for induced expression of antioxidant and other cytoprotective genes. siRNA knockdown of Nrf2 abrogated 15d-PGJ2-induced GCLC expression. Following 15d-PGJ2 treatment, the intracellular GSH level was initially diminished but eventually enhanced even above the basal level. The reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) abolished the 15d-PGJ2-induced Nrf2 activation and GCLC expression. Pharmacologic inhibition or siRNA knockdown of Akt, the target of phosphoinositide 3-kinase (PI3-K), at...