title: 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: OBJECTIVE
  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-x03BA;B 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.
  
  
  CONCLUSIONS
  Melatonin induced apoptosis in AGS cells by activating the caspase-dependent apoptotic pathway and by inhibiting the nuclear translocation of NF-x03BA;B 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.
authors.forename: Weimin
authors.initials: W
authors.lastname: Li
authors.forename: Mengdi
authors.initials: M
authors.lastname: Fan
authors.forename: Yina
authors.initials: Y
authors.lastname: Chen
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Caiyun
authors.initials: C
authors.lastname: Song
authors.forename: Ye
authors.initials: Y
authors.lastname: Yan
authors.forename: Yin
authors.initials: Y
authors.lastname: Jin
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Huang
authors.forename: Chunjing
authors.initials: C
authors.lastname: Lin
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Wu
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D004357:Drug Synergism; D004789:Enzyme Activation; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008550:Melatonin / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008550:Melatonin; D002945:Cisplatin