Abstract
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 Ca2+ 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 Ca2+ 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.
Highlights
Adrenocortical carcinoma (ACC) is a kind of malignant tumor with low incidence but poor prognosis
NCI–H295 R cells were spindle in shape and showed characteristics of hyper chromatic nuclei (Figure 1(a)), while SW-13 cells were viable cell (%) viable cell (%)
SW-13 cells (10×, scale bar is 400 μm). (c, d) H295 R and SW-13 cells were cultured with Sal at concentrations of 0, 50, 100, 150, and 200 μm for 0, 12, 24, 36, and 48 h
Summary
Adrenocortical carcinoma (ACC) is a kind of malignant tumor with low incidence but poor prognosis. ACC in most patients has already metastasized when the disease is diagnosed, and the risk of recurrence is very common after standard systemic therapies [1]. The most optimal strategy for adrenocortical cancer is surgery, but most patients have lost the opportunity for surgical treatment by the time they are diagnosed, and the cancer is often insensitive to radiotherapy and chemotherapy. Drug therapy has emerged as an effective therapeutic strategy. It still remained challenge due to the lack of effective therapeutic target. Erefore, to explore new therapeutic target for treatment of adrenocortical carcinoma is urgently needed. Extracted from human ACC tissue, the SW-13 cell line has been used for most of the basic research on anticancer drugs and cancer cell signaling pathways. Extracted from human ACC tissue, the SW-13 cell line has been used for most of the basic research on anticancer drugs and cancer cell signaling pathways. e NCI–H295 R cell line, obtained from human ACC patient, has secretion function and is widely used in the study of ACC [2]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
