Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.
PLoS One. 2018 Dec 17;13(12):e0208094. doi: 10.1371/journal.pone.0208094. eCollection 2018.
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.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的凋亡抵抗已在一些癌细胞中报道，包括AGS 人胃腺癌细胞。降低这种抵抗可能有助于阐明人类胃腺癌的治疗方法。在这项研究中，我们研究了糖原合酶激酶-3（GSK-3）抑制剂是否可以恢复胃腺癌细胞对 TRAIL 的反应性。分析了两种 GSK-3 抑制剂 SB-415286 和 LiCl 对 TRAIL 在人胃腺癌细胞系和原代胃上皮细胞中的凋亡信号的影响。这两种抑制剂都可以通过增加半胱天冬酶-8 活性及其下游信号转导来增敏胃腺癌细胞，但不能增敏原代胃上皮细胞对 TRAIL 诱导的凋亡。添加 p53 siRNA 可以下调 GSK-3 抑制剂相关的 TRAIL 诱导的凋亡和 caspase-3 活性的增敏作用。GSK-3 抑制剂强烈激活 JNK 的磷酸化。JNK 的抑制导致更早和更强烈的凋亡，表明 JNK 的激活可能为促凋亡细胞提供抗凋亡的平衡。我们的观察表明，GSK-3 抑制剂可以使 AGS 胃腺癌细胞对 TRAIL 诱导的凋亡敏感。因此，在某些类型的胃腺癌中，GSK-3 抑制剂可能增强 TRAIL 的抗肿瘤活性，可能是治疗某些类型胃腺癌的有前途的候选药物。
