gamma-Secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway
机构:[1]Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China[2]Department of Neurosurgery, Second Affiliated Hospital of Soochow University, Suzhou 215004, China
Aim: Trans-444-(3-adamantan-1-yl-ureido)-cyalohexyloxy]-benzoic acid (t-AUCB) is a soluble epoxide hydrolase inhibitor that suppresses glioblastoma cell growth in vitro. The aim of this study was to examine whether the y-secretase inhibitor ARN-(3,5-difluorophenacety1)-1alanyl]-S-phenylglycine t-butyl ester (DAPT) could sensitize glioma cells to t-AUCB-induced apoptosis. Methods: Both U251 and U87 human glioblastoma cell lines were tested. Cell growth was assessed using the cell counting kit-8. Cell apoptosis was detected with caspase-3 activity assay kits and flow cytometry. The protein levels in the p38 MAPK/MAPKAPK2/Hsp27 pathway in the cells were analyzed using Western blots. Results: Pretreatment with DAPT (2 mu mol/L) substantially potentiated the growth inhibition caused by t-AUCB (200 pmol/L) in U251 and U87 cells. Furthermore, pretreatment with DAPT markedly increased t-AUCB-induced apoptosis of U251 and U87 cells. T-AUCB alone did not significant affect caspase-3 activity in the cells, but t-AUCB plus DAPT pretreatment caused significant increase of caspase-3 actiyity. Furthermore, pretreatment with DAPT completely blocked t-AUCB-induced phosphorylation of p38 MAPK, MAPKAPK2 and Hsp27 in the cells. Conclusion: The y-secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway, suggesting that the combination of t-AUCB and DAPT may be a potentially effective strategy for the treatment of glioblastoma.
基金:
National Natural Science Foundation of China (No 81070974 and No 81301905).
第一作者机构:[1]Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China
通讯作者:
通讯机构:[1]Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China
推荐引用方式(GB/T 7714):
Li Jun-Yang,Li Ru-Jun,Wang Han-Dong.gamma-Secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway[J].ACTA PHARMACOLOGICA SINICA.2014,35(6):825-831.doi:10.1038/aps.2013.195.
APA:
Li, Jun-Yang,Li, Ru-Jun&Wang, Han-Dong.(2014).gamma-Secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway.ACTA PHARMACOLOGICA SINICA,35,(6)
MLA:
Li, Jun-Yang,et al."gamma-Secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway".ACTA PHARMACOLOGICA SINICA 35..6(2014):825-831