15-deoxy-Delta-12,14-prostaglandin J2 induces programmed cell death of breast cancer cells by a pleiotropic mechanism.
Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been found to induce cell death in a variety of cells. In this regard, we reported recently that 15-deoxy-Delta-(12,14)-prostaglandin J2 (15dPG-J2), a specific ligand of the nuclear receptor PPARgamma, inhibits proliferation and induces cellular differentiation and apoptosis in the breast cancer cell line MCF-7. In addition to PPARgamma activation other proteins, such as NF-kappaB 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 (DeltaPsi(m)), 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.
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier, 4, 28029, Madrid, Spain.
Miguel
M
Pignatelli
Jinny
J
Sánchez-Rodríguez
Angel
A
Santos
Ana
A
Perez-Castillo
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000503:physiopathology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D018613:Microscopy, Confocal; D008870:Microtubules / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D010101:Oxygen Consumption / Q000502:physiology; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D011453:Prostaglandins / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D047492:Peroxisome Proliferator-Activated Receptors; D011453:Prostaglandins; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D020169:Caspases