15-Deoxy-Δ 12,14 -prostaglandin J 2 : The endogenous electrophile that induces neuronal apoptosis

Abstract

Prostaglandin D 2 (PGD 2 ), a major cyclooxygenase product in a variety of tissues and cells, readily undergoes dehydration to yield the bioactive cyclopentenone-type PGs of the J 2 -series, such as 15-deoxy-Δ 12,14 -PGJ 2 (15d-PGJ 2 ). The observation that the level of 15d-PGJ 2 increased in the tissue cells from patients with sporadic amyotrophic lateral sclerosis suggested that the formation of 15d-PGJ 2 may be closely associated with neuronal cell death during chronic inflammatory processes. In vitro experiments using SH-SY5Y human neuroblastoma cells revealed that 15d-PGJ 2 induced apoptotic cell death. An oligonucleotide microarray analysis demonstrated that, in addition to the heat shock-responsive and redox-responsive genes, the p53-responsive genes, such as gadd45 , cyclin G1 , and cathepsin D , were significantly up-regulated in the cells treated with 15d-PGJ 2 . Indeed, the 15d-PGJ 2 induced accumulation and phosphorylation of p53, which was accompanied by a preferential redistribution of the p53 protein in the nuclei of the cells and by a time-dependent increase in p53 DNA binding activity, suggesting that p53 accumulated in response to the treatment with 15d-PGJ 2 was functional. The 15d-PGJ 2 -induced accumulation of p53 resulted in the activation of a death-inducing caspase cascade mediated by Fas and the Fas ligand.