Melatonin inhibiting the survival of human gastric cancer cells under ER stress involving autophagy and Ras-Raf-MAPK signalling.

Abstract

Melatonin exhibits antitumour activities in the treatment of many human cancers. In the present study, we aimed to improve the therapeutic potential of melatonin in gastric cancer. Our results confirmed that melatonin dose-dependently suppressed the proliferation and necrosis, and increased G0/G1 phase arrest, apoptosis, autophagy and endoplasmic reticulum (ER) stress. The Ras-Raf-MAPK signalling pathway was activated in cells after melatonin treatment. RNA-seq was performed and GSEA analysis further confirmed that many down-regulated genes in melatonin-treated cells were associated with proliferation. However, GSEA analysis also indicated that many pathways related to metastasis were increased after melatonin treatment. Subsequently, combinatorial treatment was conducted to further investigate the therapeutic outcomes of melatonin. A combination of melatonin and thapsigargin increased the apoptotic rate and G0/G1 cell cycle arrest when compared to treatment with melatonin alone. Melatonin in combination with thapsigargin triggered the increased expression of Bip, LC3-II, phospho-Erk1/2 and phospho-p38 MAPK. In addition, STF-083010, an IRE1a inhibitor, further exacerbated the decrease in survival rate induced by combinatorial treatment with melatonin and thapsigargin. Collectively, melatonin was effective in gastric cancer treatment by modifying ER stress.

• Authors: Yongye Huang, Kexun Yuan, Meifang Tang, Jiaming Yue, Lijun Bao, Shuang Wu, Yanxin Zhang, Yin Li, Yihang Wang, Xu Ou, Jiaxin Gou, Qi Zhao, Lin Yuan
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 25 Issue 3 Pg. 1480-1492 (02 2021) ISSN: 1582-4934 [Electronic] England
• PMID: 33369155 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Melatonin

Topics

• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Endoplasmic Reticulum Stress (drug effects)
• Gene Expression Profiling
• Humans
• Melatonin (pharmacology)
• Signal Transduction (drug effects)