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.