Salubrinal Regulates the Apoptosis of Adrenocortical Carcinoma Cells via the PERK/eIF2α/ATF4 Signaling Pathway

The protein-kinase-R- (PKR-) like endoplasmic reticulum kinase (PERK) signaling pathway is a well-known promoter of cell apoptosis. In this study, we aimed to determine whether salubrinal (Sal), a selective activator of eukaryotic translation initiation factor 2 (eIF2α), can induce apoptosis of human adrenocortical carcinoma (ACC) cell via activating the PERK/eIF2α/ATF4 signaling pathway, and the potential mechanisms of this action were explored. The ACC cell lines, including SW-13 and NCI–H295 R, were used. 3-(4,5)-Dimethylthiazol(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, cell scratch experiments, flow cytometry, and JC-1 staining assays were performed to detect the cell viability, cell migration, and cell apoptosis. The expression of PERK/eIF2α/ATF4 signaling-pathway-related proteins and apoptosis-related proteins was detected by western blot (WB). Intracellular Ca(2+) ion concentration was determined by a confocal laser scanning microscope. The results showed that Sal inhibited the migration and proliferation of ACC cells. Sal remarkably increased the influx of Ca(2+) ion and the apoptosis rate of ACC cells in vitro. Furthermore, the expression levels of PERK/eIF2α/ATF4 signaling-related proteins and apoptosis-related proteins were upregulated in the treatment of Sal. The research demonstrated that Sal reduces the cell viability, increases the intracellular calcium concentration, and promotes the apoptosis of ACC cells in vitro through increasing the phosphorylation level of eIF2α and activating the PERK/eIF2α/ATF4 signaling. PERK/eIF2α/ATF4 is expected to act as a potential therapeutic target for the treatment of adrenocortical carcinoma.