The Research Of Programmed Cell Death In Pancreatic Cancer Cells Induced By Selenite

BackgroundPancreatic ductal adenocarcinoma (pancreatic cancer) is one of the most aggressive tumors with difficulty in early diagnosis and surgical removal. Chemotherapy is an important treatment for advanced pancreatic cancer. However, drugs including gemcitabine could not significantly improved the survival time. Therefore, it is of great significance in developing new chemical drugs to improve the prognosis of patients. Selenium is an essential trace element with chemopreventive potential against various cancers. More and more evidences support that selenium compounds have antitumor effect, but the exact mechanism is not clear. Programmed cell death is a genetically controlled process. Apoptosis and autophagy are two fundamental types. Recent evidences showed programmed cell death was associated with many processes such as tumor development and chemotherapy resistance. Aberrant activation of Wnt/β-catenin signaling pathway is involved in multiple processes such as tumor proliferation, apoptosis, chemresistance. However, until now, the functional and specific mechanism of selenium in pancreatic cancer has not been investigated.Objective1The effects of sodium selenite in pancreatic cancer treatment.2To explore the interaction between apoptosis and autophagy in pancreatic cancer cells induced by selenite.3The mechanism of Wnt/β-catenin pathway in selenite-induced programmed cell death.4The association of β-catenin with clinical characteristics of pancreatic cancer and the relationship betweenp-catenin and prognosis of pancreatic cancer.Methods1The effect on proliferation of sodium selenite-treated pancreatic cancer cells was investigated by CCK8assay. Flow cytometry and western blot were used to detect the programmed cell death of selenite-induced pancreatic cancer cells. Fluorescence of DCF was applied to examine the change of reactive oxygen species.2Autophagy inhibitor, activator and apoptosis inhibitors were used to interfere pancreatic cancer cells. Flow cytometry and western blot detection were used to examine the affect between apoptosis and autophagy affect.3Western blot was used to find the changes of Wnt/β-catenin signaling pathway in selenium-induced programmed cell death of pancreatic cancer cells. Overexpress P-catenin and detect the influance in apoptosis and autophagy change.4To explore the effects and associated mechanism of selenium treatment in pancreatic cancer cells in vivo.5Expression of P-catenin in pancreatic cancer was investigated by immunohistochemistry method. The association between P-catenin and clinical characteristics of pancreatic cancer was analyzed by χ2test. The relationship between P-catenin and prognosis of pancreatic ductal adenocarcinoma was studied by using the cox proportional hazards model.Results1Sodium selenite could inhibit proliferation and induce apoptosis in three pancreatic cancer cell lines of PANC-1, BxPC-3and Capan-1. At the same time, autophagy was reduced in PANC-1and enhanced in BxPC-3and Capan-1. These effect depend on drug concentration and time. The intesity of ROS all increased in PANC-1, BxPC-3and Capan-1cell lines.2Autophagy inhibitor3-MA, wortmannin and Bafilomycin A1could inhibit autophagy promote apoptosis in PANC-1cell line. The autophagy activator rapamycin activated autophagy and inhibited apoptosis. Apoptosis inhibitor-VAD-fmk promoted autophagy.by inhibit apoptosis.3Wnt/β-catenin signaling pathway changed in PANC-1, BxPC-3and Capan-1. The expression of β-catenin, GSK3β, Cyclin D1and Akt were decreased. Overexpress β-catenin could decrease apoptosis in PANC-1cell line.4Sodium selenite inhibited pancreatic cancer tumor growth in nude mice cancer model and changed the Wnt/β-catenin pathway.5High expression of P-catenin was found in54.6%pancreatic caner tissues. There was a relationship between high expression of P-catenin and histological grade, T, N, and TNM stage. High expression of P-catenin was associated with poorer prognosis..ConclusionsSodium selenite inhibits the proliferation, induces apoptosis of pancreatic cancer cells. Apoptosis and autophagy interact with each other in selenium-treated pancreatic cancer cells. Wnt/p-catenin pathway plays an important role in the process.of programmed cell death in pancreatic cancer.