prostaglandin-a1 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

Prostaglandins of the A type (PGA) induce the synthesis of 70 kDa heat shock proteins (hsp70) in a large variety of mammalian cells. Induction of hsp70 has been associated with a cytoprotective effect of PGA1 after virus infection or thermal injury. In the present report we provide evidence that, in murine myoblasts, PGA1 is not able to induce hsp70 expression, whereas it increases the synthesis of the constitutive protein, hsc70, and dramatically induces the synthesis of a 32 kDa protein (p32). The p32 protein has been identified as haem oxygenase. PGA1 acts at the transcriptional level by inducing haem oxygenase mRNA synthesis, and the signal for induction appears to be associated with decreased intracellular GSH levels. Haem oxygenase, a low-molecular-mass stress protein induced in mammalian cells by oxidant stress, is known to be part of a general inducible antioxidant defence pathway. The fact that prostaglandin synthesis is stimulated in muscle during contraction and in the heart in response to ischaemia raises the possibility that induction of haem oxygenase by PGA in myoblasts could be part of a protective mechanisms in operation during stress and hypoxia.

Topics: Animals; Arsenites; Cell Line; Electrophoresis, Gel, Two-Dimensional; Enzyme Induction; Glutathione; Heat-Shock Proteins; Heme Oxygenase (Decyclizing); Hot Temperature; Mice; Muscle Proteins; Muscles; Prostaglandins A; Sodium Compounds