SIRT1 inhibition by melatonin exerts antitumor activity in human osteosarcoma cells

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 activily of melalonin. Melalonin treatment. resulted in strong antitumor activily, as evidenced no 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, melalonin Lrealment. down-regulated SIRT1 and up regulated acetylated-p53. Sirtinol (a known SIRT1 inhibilor) and SIRT1 siRNA further enhanced the antitumor activily of melalonin, while SRT1720 (a known SIRT1 activator) attenuated the antitumor activily of melatonin. In summary, melalonin is a potent inhibilor 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. (C) 2013 Elsevier B.V. All rights reserved.