title: Melatonin uptake through glucose transporters: a new target for melatonin inhibition of cancer.
abstract: Melatonin is present in a multitude of taxa and it has a broad range of biological functions, from synchronizing circadian rhythms to detoxifying free radicals. Some functions of melatonin are mediated by its membrane receptors but others are receptor-independent. For the latter, melatonin must enter into the cell. Melatonin is a derivative of the amino acid tryptophan and reportedly easily crosses biological membranes due to its amphipathic nature. However, the mechanism by which melatonin enters into cells remains unknown. Changes in redox state, endocytosis pathways, multidrug resistance, glycoproteins or a variety of strategies have no effect on melatonin uptake. Herein, it is demonstrated that members of the SLC2/GLUT family glucose transporters have a central role in melatonin uptake. When studied by docking simulation, it is found that melatonin interacts at the same location in GLUT1 where glucose does. Furthermore, glucose concentration and the presence of competitive ligands of GLUT1 affect the concentration of melatonin into cells. As a regulatory mechanism, melatonin reduces the uptake of glucose and modifies the expression of GLUT1 transporter in prostate cancer cells. More importantly, glucose supplementation promotes prostate cancer progression in TRAMP mice, while melatonin attenuated glucose-induced tumor progression and prolonged the lifespan of tumor-bearing mice. This is the first time that a facilitated transport of melatonin is suggested. In fact, the important role of glucose transporters and glucose metabolism in cell fate might explain some of the diverse functions described for melatonin.
authors.affiliation: Departamento de Morfología y Biología Celular, Instituto Universitario Oncológico del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Hevia
authors.forename: Pedro
authors.initials: P
authors.lastname: González-Menéndez
authors.forename: Isabel
authors.initials: I
authors.lastname: Quiros-González
authors.forename: Ana
authors.initials: A
authors.lastname: Miar
authors.forename: Aida
authors.initials: A
authors.lastname: Rodríguez-García
authors.forename: Dun-Xian
authors.initials: DX
authors.lastname: Tan
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.forename: Juan C
authors.initials: JC
authors.lastname: Mayo
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Sainz
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D005947:Glucose / Q000009:adverse effects / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism*; D006801:Humans; D008297:Male; D008550:Melatonin / Q000378:metabolism* / Q000627:therapeutic use; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D051381:Rats
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D005947:Glucose; D008550:Melatonin
keywords: Melatonin; cancer; glucose; glucose transporter; prostate; transgenic adenocarcinoma of the mouse prostate; transporter