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

Yi-Ying Wu; Chin-Tung Hsieh; Ying-Ming Chiu; Shen-Chieh Chou; Jung-Ta Kao; Dong-Chen Shieh; Yi-Ju Lee

doi:10.1371/journal.pone.0208094

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

PLoS One. 2018 Dec 17;13(12):e0208094. doi: 10.1371/journal.pone.0208094. eCollection 2018.

Authors

Yi-Ying Wu^{1

2

3}, Chin-Tung Hsieh⁴, Ying-Ming Chiu^{5

6}, Shen-Chieh Chou⁷, Jung-Ta Kao^{8

9}, Dong-Chen Shieh⁵, Yi-Ju Lee¹⁰

Affiliations

¹ Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
² Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.
³ Research Center for Chinese Herbal Medicine, China Medical University, Taichung, Taiwan.
⁴ Department of Pediatrics, Lo-Hsu Medical Foundation Lotung Poh-Ai Hospital, I-Lan, Taiwan.
⁵ Department of Nursing, College of Medicine and Nursing, Hungkuang University, Taichung, Taiwan.
⁶ Division of Allergy, Immunology & Rheumatology, Changhua Christian Hospital, Changhua, Taiwan.
⁷ Department of Biological Science and Technology, School of Medicine, China Medical University, Taichung, Taiwan.
⁸ Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
⁹ Department of Internal Medicine, School of Medicine, China Medical University Hospital and China Medical University, Taichung, Taiwan.
¹⁰ Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Grants and funding

This work was financially supported by the “Chinese Medicine Research Center, China Medical University” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan (CMU107-CR-02) (CMRC-CHM-5), the Ministry of Health and Welfare, Taiwan (MOHW107-TDU-B-212-123004), and the National Science Council, Taiwan (NSC 98-2320-B-039 -012 -MY3).