Journal Article

15-Deoxy-Δ-<sup>12,14</sup>-prostaglandin J<sub>2</sub> induces programmed cell death of breast cancer cells by a pleiotropic mechanism

Miguel Pignatelli, Jinny Sánchez-Rodríguez, Angel Santos and Ana Perez-Castillo

in Carcinogenesis

Volume 26, issue 1, pages 81-92
Published in print January 2005 | ISSN: 0143-3334
Published online January 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh308
15-Deoxy-Δ-12,14-prostaglandin J2 induces programmed cell death of breast cancer cells by a pleiotropic mechanism

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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.

Keywords: 15dPG-J2, 15-deoxy-Δ-12,14-prostaglandin J2; FCCP, p-(trifluoromethoxy)phenylhydrazone; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; TMRE, tetramethylrhodamine methyl ester perclorate

Journal Article.  7135 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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