Melatonin Induces Cell Apoptosis in AGS Cells Through the Activation of JNK and P38 MAPK and the Suppression of Nuclear Factor-Kappa B: a Novel Therapeutic Implication for Gastric Cancer

Abstract

Background/Aims: Melatonin, synthesized by the pineal gland and released into the blood, appears to have antitumour properties; however, the mechanisms of its anti-cancer effects are largely unknown, especially in stomach cancer. Here, we explore the antitumour activity of melatonin in a gastric cancer cell line (AGS) and analyse its molecular mechanisms. Methods: AGS cells were treated with melatonin, and cell viability was assessed using a CCK-8 assay. Flow cytometry was performed to evaluate apoptosis, and protein expression was examined by Western blotting. Results: Melatonin significantly inhibited cell viability, clone formation, and cell migration and invasion and induced apoptosis in AGS cells. Moreover, MAPK pathways (p38, JNK and ERK) were activated by melatonin treatment, which also significantly increased caspase-3 cleavage and Bax protein expression and decreased Bcl-2 protein expression in a time-dependent manner. Our results demonstrate that p38 and JNK inhibitors (SB203580 and SP600125, respectively) prevented melatonin-induced apoptosis; thus, the propensity of p38 MAPK and JNK to promote apoptosis could be at least partly due to the inhibition of NF-κB p65 activation by p38 and JNK. Finally, melatonin was able to strengthen cisplatin-mediated antitumour effects in human gastric carcinoma cells by up-regulating the expression of Bax, down-regulating the expression of Bcl-2 and activating the caspase-dependent apoptotic pathway. Conclusion: Melatonin induced apoptosis in AGS cells by activating the caspase-dependent apoptotic pathway and by inhibiting the nuclear translocation of NF-κB p65, two processes that are regulated by p38 and JNK. Furthermore, melatonin significantly enhanced the anti-tumour effects of cisplatin, with low systemic toxicity. These new findings suggest that melatonin may act as a potent anti-tumour agent and may have great potential as an adjuvant therapy in the future.

A Crosstalk between Melatonin and Taste-Receptors’ Signaling Tunes Quinine-Induced Gut Hormone Secretion in Mice

“…Moreover, they express MNTRs and thus represents a suitable in vitro biological system for our analysis [38,39]. As expected, treatment with quinine induced Ghrelin secretion in AGS cells ( Figure 4C).…”

Knockdown of PD-L1 in Human Gastric Cancer Cells Inhibits Tumor Progression and Improves the Cytotoxic Sensitivity to CIK Therapy

“…Recently, with the development of therapeutic treatments of gastric cancer, antitumor drugs and immunotherapy strategies, especially the immune checkpoint intervention, have made breakthrough progress [37, 38]. The cancer immunotherapy based on PD-L1 targeting has provided major breakthroughs in clinical trials in multiple human cancers [11, 39].…”

The melatonin immunomodulatory actions in radiotherapy

“…The anti-proliferative effect of melatonin may be related to negative regulation of NF-κB. This factor has proliferative effects by its direct action on cyclin D1 (Li et al 2015). Also, melatonin induces apoptosis by activating the caspase-dependent apoptotic pathway, enhancing tumor necrosis factor, downregulating Bcl-2, and survival, by inhibiting the nuclear translocation of NF-κB p65 (Sainz et al 2008;Joo and Yoo 2009).…”