title: Distinct roles of N-acetyl and 5-methoxy groups in the antiproliferative and neuroprotective effects of melatonin.
abstract: Melatonin (N-acetyl-5-methoxytryptamine) is a highly pleiotropic hormone with antioxidant, antiproliferative, oncolytic and neuroprotective properties. Here, we present evidence that the N-acetyl side chain plays a key role in melatonin's antiproliferative effect in HT22 and sw-1353 cells, but it does so at the expense of antioxidant and neuroprotective properties. Removal of the N-acetyl group enhances the antioxidant and neuroprotective properties of the indole, but it can lead to toxic methamphetamine-like effects in several cell lines. Inhibition of NFkB mimicked melatonin's antiproliferative and antioxidant effects, but not neuroprotection. Our results strongly suggest that neuroprotective and antiproliferative effects of melatonin rely on different parts of the molecule and are likely mediated by different mechanisms. We also predict that melatonin metabolism by target cells could determine whether melatonin inhibits cell proliferation, prevents toxicity or induces cell death (e.g. apoptosis or autophagy). These observations could have important implications for the rational use of melatonin in personalized medicine.
authors.affiliation: Cell Structure and Dynamics Laboratory, Instituto de Tecnologia Quimica e Biologica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Letra-Vilela
authors.affiliation: Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Sánchez-Sánchez
authors.affiliation: Cell Structure and Dynamics Laboratory, Instituto de Tecnologia Quimica e Biologica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal.
authors.forename: Ana Maia
authors.initials: AM
authors.lastname: Rocha
authors.affiliation: Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Martin
authors.affiliation: Cell Structure and Dynamics Laboratory, Instituto de Tecnologia Quimica e Biologica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Branco-Santos
authors.affiliation: Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Puente-Moncada
authors.affiliation: Cell Structure and Dynamics Laboratory, Instituto de Tecnologia Quimica e Biologica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal.
authors.forename: Mariana
authors.initials: M
authors.lastname: Santa-Marta
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Center Gottingen, Waldweg 33, 37073 Gottingen, Germany; Max Planck Institute for Experimental Medicine, 37075 Goettingen, Germany.
authors.forename: Tiago Fleming
authors.initials: TF
authors.lastname: Outeiro
authors.affiliation: Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Isaac
authors.initials: I
authors.lastname: Antolín
authors.affiliation: Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain. Electronic address: carro@uniovi.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Rodriguez
authors.affiliation: Cell Structure and Dynamics Laboratory, Instituto de Tecnologia Quimica e Biologica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal. Electronic address: fherrera@itqb.unl.pt.
authors.forename: Federico
authors.initials: F
authors.lastname: Herrera
mesh_terms: D008735:5-Methoxytryptamine; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001343:Autophagy; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018698:Glutamic Acid / Q000633:toxicity*; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D018698:Glutamic Acid; D008735:5-Methoxytryptamine; D008550:Melatonin
keywords: 5-Methoxy; Autophagy; Cell proliferation; Melatonin; N-acetyl; Neuroprotection