GSK-3 inhibitors enhance TRAIL-mediated apoptosis in human gastric adenocarcinoma cells.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Adenocarcinoma/*drug therapy ; Apoptosis/*drug effects ; Glycogen Synthase Kinase 3/*antagonists & inhibitors ; Protein Kinase Inhibitors/*pharmacology ; Stomach Neoplasms/*drug therapy; Adenocarcinoma/pathology ; Aminophenols/pharmacology ; Aminophenols/therapeutic use ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Glycogen Synthase Kinase 3/genetics ; Glycogen Synthase Kinase 3/metabolism ; Humans ; Lithium Chloride/pharmacology ; Lithium Chloride/therapeutic use ; Maleimides/pharmacology ; Maleimides/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; RNA, Small Interfering/metabolism ; Stomach Neoplasms/pathology ; TNF-Related Apoptosis-Inducing Ligand/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism

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.
Competing Interests: The authors have declared that no competing interests exist.

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0 (3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione)
0 (Aminophenols)
0 (Maleimides)
0 (Protein Kinase Inhibitors)
0 (RNA, Small Interfering)
0 (TNF-Related Apoptosis-Inducing Ligand)
0 (TNFSF10 protein, human)
0 (TP53 protein, human)
0 (Tumor Suppressor Protein p53)
EC 2.7.11.26 (Glycogen Synthase Kinase 3)
G4962QA067 (Lithium Chloride)

Date Created: 20181218 Date Completed: 20190522 Latest Revision: 20200309

20240105

PMC6296518

10.1371/journal.pone.0208094

30557366