Human transporters, PEPT1/2, facilitate melatonin transportation into mitochondria of cancer cells: An implication of the therapeutic potential.

Melatonin is present in virtually all organisms from bacteria to mammals, and it exhibits a broad spectrum of biological functions, including synchronization of circadian rhythms and oncostatic activity. Several functions of melatonin are mediated by its membrane receptors, but others are receptor-independent. For the latter, melatonin is required to penetrate membrane and enters intracellular compartments. However, the mechanism by which melatonin enters cells remains debatable. In this study, it was identified that melatonin and its sulfation metabolites were the substrates of oligopeptide transporter (PEPT) 1/2 and organic anion transporter (OAT) 3, respectively. The docking analysis showed that the binding of melatonin to PEPT1/2 was attributed to their low binding energy and suitable binding conformation in which melatonin was embedded in the active site of PEPT1/2 and fitted well with the cavity in three-dimensional space. PEPT1/2 transporters play a pivotal role in melatonin uptake in cells. Melatonin's membrane transportation via PEPT1/2 renders its oncostatic effect in malignant cells. For the first time, PEPT1/2 were identified to localize in the mitochondrial membrane of human cancer cell lines of PC3 and U118. PEPT1/2 facilitated the transportation of melatonin into mitochondria. Melatonin accumulation in mitochondria induced apoptosis of PC3 and U118 cells. Thus, PEPT1/2 can potentially be used as a cancer cell-targeted melatonin delivery system to improve the therapeutic effects of melatonin in cancer treatment.

Mechanism of action and promising clinical application of melatonin from a dermatological perspective.

Melatonin is the main neuroendocrine product in the pineal gland. Melatonin can regulate circadian rhythm-related physiological processes. Evidence indicates an important role of melatonin in hair follicles, skin, and gut. There appears to be a close association between melatonin and skin disorders. In this review, we focus on the latest research of the biochemical activities of melatonin (especially in the skin) and its promising clinical applications.

Melatonin Target Proteins: Too Many or Not Enough?

The neurohormone N-acetyl-5-methoxytryptamine, better known as melatonin, is a tryptophan derivative with a wide range of biological effects that is present in many organisms. These effects are believed to rely either on the chemical properties of melatonin itself as scavenger of free radicals or on the binding of melatonin to protein targets. More than 15 proteins, including receptors (MT1, MT2, Mel1c, CAND2, ROR, VDR), enzymes (QR2, MMP-9, pepsin, PP2A, PR-10 proteins), pores (mtPTP), transporters (PEPT1/2, Glut1), and other proteins (HBS, CaM, tubulin, calreticuline), have been suggested to interact with melatonin at sub-nanomolar to millimolar melatonin concentrations. In this review we assemble for the first time the available information on proposed melatonin targets and discuss them in a comprehensive manner to evaluate the robustness of these findings in terms of methodology, physiological relevance, and independent replication.