15-deoxyprostaglandin-j2 and sodium-arsenite

The signaling lipid molecule 15-deoxy-delta 12,14-prostaglandin J2 (15d-PGJ2) has multiple cellular functions, including anti-inflammatory and antineoplastic activities. Here, we report that 15d-PGJ2 blocks translation through inactivation of translational initiation factor eIF4A. Binding of 15d-PGJ2 to eIF4A blocks the interaction between eIF4A and eIF4G that is essential for translation of many mRNAs. Cysteine 264 in eIF4A is the target site of 15d-PGJ2. The antineoplastic activity of 15d-PGJ2 is likely attributed to inhibition of translation. Moreover, inhibition of translation by 15d-PGJ2 results in stress granule (SG) formation, into which TRAF2 is sequestered. The sequestration of TRAF2 contributes to the anti-inflammatory activity of 15d-PGJ2. These findings reveal a novel cross-talk between translation and inflammatory response, and offer new approaches to develop anticancer and anti-inflammatory drugs that target translation factors including eIF4A.

Topics: Anti-Inflammatory Agents; Arachidonic Acid; Arsenites; Chromans; Cyclopentanes; Cytoplasmic Granules; Dinoprostone; Emetine; Enzyme Inhibitors; Eukaryotic Initiation Factor-2; Eukaryotic Initiation Factor-4A; Gene Expression Regulation; HeLa Cells; Humans; Hypoglycemic Agents; Inflammation; Poly(A)-Binding Proteins; PPAR gamma; Prostaglandin D2; Prostaglandins A; Protein Biosynthesis; Protein Synthesis Inhibitors; Rosiglitazone; Signal Transduction; Sodium Compounds; T-Cell Intracellular Antigen-1; Thiazolidinediones; TNF Receptor-Associated Factor 2; Troglitazone; Tumor Necrosis Factor-alpha