Abstract
Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis has been reported in some cancer cells, including AGS human gastric adenocarcinoma cells. Reducing this resistance might shed light on the treatment of human gastric adenocarcinoma. In this study, we examined whether glycogen synthase kinase-3 (GSK-3) inhibitors can restore TRAIL responsiveness in gastric adenocarcinoma cells. The effect of two GSK-3 inhibitors, SB-415286, and LiCl, on apoptosis signaling of TRAIL in human gastric adenocarcinoma cell lines and primary gastric epithelial cells was analyzed. Both inhibitors can sensitize gastric adenocarcinoma cells, but not primary gastric epithelial cells, to TRAIL-induced apoptosis by increasing caspase-8 activity and its downstream signal transmission. Adding p53 siRNA can downregulate GSK-3 inhibitor-related sensitization to TRAIL-induced apoptosis and caspase-3 activity. GSK-3 inhibitors strongly activate the phosphorylation of JNK. Inhibition of JNK leads to earlier and more intense apoptosis, showing that the activation of JNK may provide anti-apoptotic equilibrium of pro-apoptotic cells. Our observations indicate that GSK-3 inhibitors can sentize AGS gastric adenocarcinoma cells to TRAIL-induced apoptosis. Therefore, in certain types of gastric adenocarcinoma, GSK-3 inhibitor might enhance the antitumor activity of TRAIL and mightbe a promising candidate for the treatment of certain types of gastric adenocarcinoma.
Highlights
Gastric cancer is a malignant neoplasm with poor prognosis [1]
Effects of glycogen synthase kinase-3 inhibitor on apoptosis induced by agonistic anti-CD95 antibodies (CH-11) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in gastric adenocarcinoma cell Line AGS
glycogen synthase kinase-3 (GSK-3) in human gastric adenocarcinoma cells enhanced the percentage of sub-G1 population, while TRAIL alone can enhance the percentage to 27.8±6% (Fig 1A)
Summary
Gastric cancer is a malignant neoplasm with poor prognosis [1]. Surgical treatment is currently the only option which offers curative potential to patients with locally advanced gastric cancer [2]. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a novel TNF superfamily member with strong homology to FasL, is capable of inducing apoptosis in a variety of transformed cell lines in vitro [3]. Recent studies indicated that TRAIL-induced apoptosis occurred through a caspase signaling cascade [4]. Resistance to TRAIL-induced apoptosis has been reported in some cancer cells, including AGS human gastric adenocarcinoma cells [5,6]. The restoration of TRAIL-induced apoptosis sensitivity might offer a new treatment option for human gastric adenocarcinoma
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