Carcinogenesis Advance Access first published online on October 14, 2004
This version published online on October 21, 2004
Carcinogenesis, doi:10.1093/carcin/bgh308
© 2004 by Oxford University Press
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1 Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier, 4, 28029-Madrid
* To whom correspondence should be addressed. Activation of PPAR
Revised September 9, 2004
Accepted October 1, 2004
CANCER BIOLOGY
15-deoxy-
-12,14-prostaglandin J2 induces programmed cell death of breast cancer cells by a pleiotropic mechanism
2 Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier, 4, 28029-Madrid; Sección de Investigaciones Metabólicas y Nutricionales, Instituto de Medicina Experimental, Universidad Central de Venezuela
3 Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid
Ana Perez-Castillo, E-mail: aperez{at}iib.uam.es
Abstract 
had 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, 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 overexpression and zVAD fmk, 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.
The originally published version of this paper was incorrect. The figures were missing. The author apologises for this error.
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