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Melatonin uptake through glucose transporters: a new target for melatonin inhibition of cancer
Author(s) -
Hevia David,
GonzálezMenéndez Pedro,
QuirosGonzález Isabel,
Miar Ana,
RodríguezGarcía Aida,
Tan DunXian,
Reiter Russel J.,
Mayo Juan C.,
Sainz Rosa M.
Publication year - 2015
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12210
Subject(s) - melatonin , glut1 , glucose transporter , biology , endocrinology , medicine , glucose uptake , receptor , biochemistry , chemistry , insulin
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 SLC 2/ 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 GLUT 1 where glucose does. Furthermore, glucose concentration and the presence of competitive ligands of GLUT 1 affect the concentration of melatonin into cells. As a regulatory mechanism, melatonin reduces the uptake of glucose and modifies the expression of GLUT 1 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.