Carcinogenesis Advance Access originally published online on October 14, 2004
Carcinogenesis 2005 26(1):81-92; doi:10.1093/carcin/bgh308
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Carcinogenesis vol.26 no.1 © Oxford University Press 2005; all rights reserved.
ARTICLE |
15-Deoxy-
-12,14-prostaglandin J2 induces programmed cell death of breast cancer cells by a pleiotropic mechanism
1 Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier, 4, 28029, Madrid, Spain, 2 Sección de Investigaciones Metabólicas y Nutricionales, Instituto de Medicina Experimental, Universidad Central de Venezuela, Venezuela and 3 Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
4 To whom correspondence should be addressed Email: aperez{at}iib.uam.es or piedras3{at}med.ucm.es
Activation of peroxisome proliferator-activated receptor 
(PPAR) has been found to induce cell death in a variety of cells. In this regard, we reported recently that 15-deoxy-
-12,14-prostaglandin J2 (15dPG-J2), a specific ligand of the nuclear receptor PPAR, inhibits proliferation and induces cellular differentiation and apoptosis in the breast cancer cell line MCF-7. In addition to PPAR activation other proteins, such as NF-
B 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 (
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.
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