title: SIRT1 inhibition by melatonin exerts antitumor activity in human osteosarcoma cells.
abstract: Melatonin, the main secretory product of the pineal gland, has potent antitumor activity against various types of cancer. However, the molecular mechanisms underlying the effects of melatonin remain largely unknown. SIRT1, a conserved nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase, has been implicated in modulating transcriptional silencing and cell survival and plays a key role in carcinogenesis through the deacetylation of important regulatory proteins. In this study, we assessed the antitumor activity of melatonin against human osteosarcoma cells (9607 cell line) and explored the role of SIRT1 in the activity of melatonin. Melatonin treatment resulted in strong antitumor activity, as evidenced not only by reductions in tumor cell vitality, adhesion ability, migration ability and glutathione (GSH) levels but also by increase in the apoptotic index and reactive oxygen species. Additionally, melatonin treatment down-regulated SIRT1 and up-regulated acetylated-p53. Sirtinol (a known SIRT1 inhibitor) and SIRT1 siRNA further enhanced the antitumor activity of melatonin, while SRT1720 (a known SIRT1 activator) attenuated the antitumor activity of melatonin. In summary, melatonin is a potent inhibitor of osteosarcoma cell growth that targets SIRT1 signaling, and the inhibition of SIRT1 signaling is a novel mechanism of action for melatonin during therapeutic intervention in osteosarcoma.
authors.affiliation: Department of Orthopaedics, the 82th Hospital of PLA, 100# Jiangkang Road, Huai'an 213002, China.
authors.forename: Yedong
authors.initials: Y
authors.lastname: Cheng
authors.forename: Liping
authors.initials: L
authors.lastname: Cai
authors.forename: Peng
authors.initials: P
authors.lastname: Jiang
authors.forename: Jiabo
authors.initials: J
authors.lastname: Wang
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.forename: Haibo
authors.initials: H
authors.lastname: Feng
authors.forename: Changchao
authors.initials: C
authors.lastname: Wang
authors.forename: Haiyuan
authors.initials: H
authors.lastname: Pan
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D012516:Osteosarcoma / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D017382:Reactive Oxygen Species; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D005978:Glutathione; D008550:Melatonin
keywords: Antitumor; Melatonin; Osteosarcoma; SIRT1; p53