Novel regulator role of CIL-102 in the epigenetic modification of TNFR1/TRAIL to induce cell apoptosis in human gastric cancer. (January 2021)

• Record Type: Journal Article
• Authors: Teng, Chih-Chuan; Tung, Shui-Yi; Lee, Ko-Chao; Lee, Kam-Fai; Huang, Wen-Shih; Shen, Chien-Heng; Hsieh, Meng-Chiao; Huang, Cheng-Yi; Sheen, Jiunn-Ming; Kuo, Hsing-Chun
• Is Part Of: Food and chemical toxicology. Volume 147(2021)
• Publication Date: 2021-01
• Subjects: CIL-102 -- Gastric cancer cells -- Apoptosis -- Death receptors -- H3K4me3; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2020.111856
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: CIL-102 (1-[4-(furo [2, 3-b]quinolin-4-ylamino)phenyl]ethanone) is a major active agent and an alkaloid derivative of Camptotheca acuminata, which has valuable biological properties, including anti-tumorigenic activity. However, the molecular mechanisms of CIL-102 related to inductive apoptosis in human gastric cancer remain unclear. By using diphenyltetrazolium bromide (MTT), annexin-V–fluorescein-isothiocyanate (FITC)/propidium iodide staining and a 2′, 7' –dichlorofluorescin diacetate (DCFDA), a Fluo-3 fluorescence staining assay, the cell death and cell viability in gastric cancer cells and an in vivo xenograft mouse model, with or without the addition of CIL-102, were measured, respectively. Furthermore, signaling pathways and apoptotic molecules were also detected by western blots and an immunohistochemical assay. Our results demonstrated that CIL-102 treatment significantly induced the cell apoptosis of gastric cancer cells, along with increased ROS production and increased intracellular Ca2+ levels. In addition, through the inactivation of CDK1/cyclin B1, CIL-102 treatment induced the cell cycle G2/M arrest of gastric cancer cells. Moreover, our data revealed that multiple signaling pathways were involved in the H3K4 trimethylation of TNFR1 and TRAIL proteins by CIL-102, including ROS-derived and JNK/mTOR/p300 pathways in gastric cancer AGS cells. The CIL-102 treatment also consistently inhibited tumor growth and increased tumor apoptosis, as measured by TUNEL assay in an in vivo xenograft mouse model. An immunohistochemical analysis revealed that the upregulation of the TNFR1 and TRAIL proteins and the downregulation of PCNA and CDK1 proteins were found in the CIL-102-treated gastric cancer xenograft mouse model, compared to that of the saline control. Together, this study sheds light on the novel mechanism associated with CIL-102 for inducing gastric cancer apoptosis. Graphical abstract: Schematic presentation of the molecular mechanism underlying CIL-102 that induces cell apoptosis of AGS gastric cancer cells. Image 1 Highlights: Induction of cell apoptosis by CIL-102 in human gastric cancer cells. CIL-102 treatment may lead to cell cycle G2/M arrest of AGS cells. CIL-102 treatment induces histone H3 trimethylation at the promoter region of TNFR1 and TRAIL.