15-Deoxy-Δ-12,14-prostaglandin J2 induces programmed cell death of breast cancer cells by a pleiotropic mechanism

Abstract

Activation of peroxisome proliferator-activated receptor γ (PPARγ) has been found to induce cell death in a variety of cells. In this regard, we reported recently that 15-deoxy-Δ-12,14-prostaglandin J2 (15dPG-J2), a specific ligand of the nuclear receptor PPARγ, inhibits proliferation and induces cellular differentiation and apoptosis in the breast cancer cell line MCF-7. In addition to PPARγ activation other proteins, such as NF-κB and AP1, have been shown to be targets of 15dPG-J2. However, the mechanism by which 15dPG-J2 triggers cell death is still elusive. Our results demonstrate that 15dPG-J2 initiates breast cancer cell death via a very rapid and severe impairment of mitochondrial function, as revealed by a drop in mitochondrial membrane potential (ΔΨm), generation of reactive oxygen species (ROS) and a decrease in oxygen consumption. In addition, 15dPG-J2 can also activate an intrinsic apoptotic pathway involving phosphatidyl serine externalization, caspase activation and cytochrome c release. Bcl-2 over-expression and zVADfmk, albeit preventing caspase activation, have no effect on 15dPG-J2-mediated mytochondrial dysfunction and loss of cell viability. In contrast, the addition of radical scavengers or rotenone, which prevent 15dPG-J2-induced ROS production, block the loss of cell viability induced by this prostaglandin. Finally, 15dPG-J2-induced cell death appears to involve disruption of the microtubule cytoskeletal network. Together, these results suggest that PG-J2-induced mitochondrial dysfunction and ROS production inevitably leads to death, with or without caspases. © Oxford University Press 2005; all rights reserved.