A apoptose induzida pelo anti-inflamatório não esteróide salicilato de sódio requer a participação da proteína cinase gcn2 e o envolvimento de vias do estresse do retículo endoplasmático

Abstract

Salicylates are non-steroidal anti-inflammatory drugs with the well-known ability to inhibit cyclooxygenase activity, the key enzyme in prostaglandin biosynthesis. The salicylates also induce the phosphorylation of the alpha-subunit of eukaryotic translation initiation factor (eiF2 alpha). Under different stress conditions, kinases such as PERK and GCN2 can phosphorylate eIF2 alpha and trigger the activation of signaling pathways such as the unfolded protein response (UPR) elicited in the endoplasmic reticulum. In addition to their anti-inflammatory actions, salicylates have been reported to induce apoptosis in a number of cell types by regulating multiple molecules. In this study we wanted to identify genes related to the UPR that are activated upon sodium salicylate (NaSal) treatment and determine the possible role of the eIF2 alpha kinase GCN2 in the cell death induced by NaSal. Transcriptional profiling by PCR array was used to compare 84 mRNAs in untreated and NaSal treated wild type and GCN2-/- mouse embryonic fibroblasts (MEFs). We found that NaSal treatment strongly induces apoptosis of wild-type, but to a much less extent in GCN2-/-MEFs. NaSal treatment led to the induction of several UPR responsive genes, especially involved in apoptosis, transcriptional regulation and metabolism. The transcriptional activation of the pro-apoptotic transcription factor CHOP/GADD153, the most highly expressed gene induced upon NaSal treatment, was dependent on GCN2. GCN2 loss in cells renders them resistant to apoptosis induced by salicylates. We conclude that the GCN2 kinase plays a key role in cell death induced by NaSal treatment by regulating a number of genes in the UPR pathway