Investigation of the effects of IRE1α, the endoplasmic reticulum stress factor, on cell death in pancreatic cancer cells.

Objective: In this study, it was aimed to determine the effects of IRE1α, an endoplasmic reticulum stress factor, on pancreatic cancer. Materials and Methods: The study was performed in vitro with the pancreatic cancer cell line Panc-1. The cell line was propagated by cell culture methods and treated with the experimental drugs gemcitabine, STF-083010 and thapsigargin. The effects of STF-083010, an IRE1α inhibitor, on cytotoxicity, apoptosis, cell cycle, caspase 3/7 and invasion in pancreatic cancer cells were tested. In addition, the effects of cell death and endoplasmic reticulum stress at the protein level were examined by western blot test. One Way Anova test was used for data analysis and Bonferroni test was used for pairwise comparison. Results: The IC50 ratio was 160 µM for STF-083010 and 4 mg/ ml for Gemcitabine. We also found that low-dose chemotherapy and STF-083010 treatment showed a synergistic effect. While %6.25 total apoptosis and %5.42 necrosis were detected in the NT group, %36.67 total apoptosis and %3.1 necrosis in the gemcitabine group, %34.97 total apoptosis and %0.97 necrosis in the STF-083010 group, %43.52 total apoptosis and %3.5 necrosis were detected in Gemcitabine + STF-083010. These results were also statistically significant. Caspase 3/7 ratio was %9.68 in the NT group, %27.7 in the Gemcitabine group, %26.12 in the STF-083010 group, and %49.84 in Gemcitabine + STF-083010. Western blot results showed an increase in pro-apoptotic Bak protein in the STF-083010 group compared to the control and gemcitabine groups. In addition, a significant decrease in the angiogenesis marker VEGFR2 was observed in the STF-083010 group compared to the control and gemcitabine groups. The anti-proliferative effect of STF-083010 was also observed in the clonogenic assay. In the invasion experiment, a decrease in the amount of metastatic cells was observed in the STF-083010 and gemcitabine + STF-083010 groups compared to the control group. Conclusion: In this study, it was concluded that pancreatic cancer cells are under ER stress and the IRE1 inhibitor STF-083010 inhibits the pro-survival pathway of this stress, causing cells to enter apoptosis. In addition, it was concluded that tumor angiogenesis (in the context of VEFGR2) is active in pancreatic cancer cells, and the use of STF-083010 may inhibit angiogenesis by causing a decrease in VEGFR2 expression.