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.

TRPV4 activation triggers the release of melatonin from human non-pigmented ciliary epithelial cells

“…It is a membrane protein that belongs to the transient receptors, which is a non-selective cation channel permeable to Ca 2þ . In this sense, the Ca 2þ influx triggered after TRPV4 stimulation is probably able to induce the release of melatonin as it occurs in other cells such as pinealocytes or retinal cells, although recently it has been demonstrated that melatonin could be transported by means of glucose transporters (Hevia et al, 2015).…”

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…This type of glucose metabolism is termed aerobic glycolysis [83], a phenomenon inhibited by melatonin, thus reducing glucose metabolism. Melatonin decreases the uptake of glucose and modifies the expression of the GLUT1 transporter in prostate cancer cells, supporting a critical role in the uptake of glucose by cancer cells [84].…”

Melatonin Mitigates Mitochondrial Meltdown: Interactions with SIRT3

“…This entry was thought to be related to simple diffusion of melatonin, which is highly lipophilic, through the plasma and mitochondrial membranes. While this possibility is still viable, melatonin has been shown to enter cells via the GLUT1 transporter [178] and by means of the PEPT1/2 oligopeptide transporters [180]. The latter proteins also exist in mitochondrial membranes where they presumably aid in the rapid uptake of melatonin against a gradient.…”

“…While this remains a possible route for its entrance into cells, recent studies have examined active transport means by which it passes through membranes. The first serious attempt to determine how high intracellular levels of melatonin are achieved, Hevia et al [178] examined the uptake of melatonin in a variety of normal and cancer cells. For this purpose, cells were incubated in a solution containing pharmacological concentrations (1 mM) of melatonin.…”