Open AccessMelatonin inhibiting the survival of human gastric cancer cells under ER stress involving autophagy and Ras‐Raf‐MAPK signalling
Author(s) -
Huang Yongye,
Yuan Kexun,
Tang Meifang,
Yue Jiaming,
Bao Lijun,
Wu Shuang,
Zhang Yanxin,
Li Yin,
Wang Yihang,
Ou Xu,
Gou Jiaxin,
Zhao Qi,
Yuan Lin
Publication year - 2021
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.16237
Subject(s) - melatonin , thapsigargin , autophagy , mapk/erk pathway , apoptosis , cancer research , cancer , medicine , endocrinology , endoplasmic reticulum , cancer cell , biology , signal transduction , microbiology and biotechnology , biochemistry
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.