MT‐1 melatonin receptor expression increases the antiproliferative effect of melatonin on S‐91 murine melanoma cells

Abstract

Melatonin, a derivative of tryptophan that is present in all vertebrates, was first described in bovine pineal gland. It is known that melatonin is a highly conserved molecule, present also in unicellular organisms and plants. Several effects of melatonin have been described, including receptor- and non-receptor-mediated actions. Herein, we studied the effects of melatonin on in vitro and in vivo cell proliferation of Cloudman S-91 murine melanoma cells. We demonstrated that melatonin treatment significantly inhibits S-91 melanoma cell proliferation in vitro (EC50 = 10-7 m) as well as reduces tumor growth in vivo. We also demonstrated that melatonin directly increases the activity of the antioxidant enzymes catalase and glutathione peroxidase. These effects are most likely triggered through the direct intracellular action of melatonin, since the presence of receptors could not be demonstrated in this cell line. Expression of MT-1 melatonin receptor by stable transfection, mediated a dramatic antiproliferative melatonin effect (EC50 = 10-10 m) in S-91 cells. The expressed receptor is negatively coupled to the adenylyl cyclase/cyclic AMP signaling pathway via Gi protein. These results suggest that expression of the MT-1 melatonin receptor in melanoma cells is a potential alternative approach to specifically target cells in cancer therapeutic treatment.

Therapeutic Actions of Melatonin in Cancer: Possible Mechanisms

“…121 In addition, the antiproliferative effect of melatonin was attributed to the stimulatory action on antioxidative enzyme synthesis. 122 High daytime serum melatonin levels (9.7 to 20.9 pg/mL) was reported in patients with melanoma as compared with normal individuals (1.4 to 2.1 pg/mL). 123 High melatonin levels were reported in patients with choroidal melanoma where melatonin levels decreased following enucleation.…”

Oncostatic effects of the indole melatonin and expression of its cytosolic and nuclear receptors in cultured human melanoma cell lines

“…For example, studies in the colon 38 carcinoma cell line identified both the nuclear receptor RZR/ROR (ROR·) and the cell membrane receptor MT2, but not MT1, as being responsible for the oncostatic effect of melatonin (41,52,68,69). In contrast, the MT1 receptor was responsible for the enhancement of the tumor suppressing effect of melatonin in MCF-7 breast cancer cells (39,53) and in S-91 murine melanoma cells (45). In uveal melanoma cell lines, melatonin and agonists for MT1 and MT2 inhibited melanoma growth, whereas the nuclear receptor was not involved in growth suppression (47).…”

“…Melanoma is an aggressive form of skin cancer associated with high mortality and limited response to therapy once extended beyond the skin (42)(43)(44). Melatonin has been shown to suppress cell growth in selected cutaneous and uveal melanoma cell lines of rodent and human origin (32,(45)(46)(47). Also clinically, there is some evidence for melatonin having potent antineoplastic activity (48)(49)(50)(51).…”

“…The biological activity of melatonin is enhanced by its strong lipophilic property that allows for easy penetration through cell membranes and the possibility of direct intracellular actions. The anticarcinogenic effect seems to be increased through membrane, cytosolic and/or nuclear receptors (45,47,52,53). The membrane receptors, represented by MT1 and MT2, belong to a G-protein coupled receptor super-family which can bind to a variety of G-proteins (54)(55)(56) and are differentially expressed in melanoma cell lines (24).…”

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

“…Melatonin administration decreases the weight and volume of S-91 melanoma tumors in mice in vivo, and melatonin inhibits S-91 cell proliferation in vitro (Kadekaro et al, 2004), which was dramatically potentiated by expression of MT 1 melatonin receptors (Kadekaro et al, 2004). Overexpression of MT 1 receptor in MCF-7 breast cancer cells facilitates melatonin-mediated tumor growth inhibition in vivo and in vitro (Collins et al, 2003) through a melatonin receptor mediated mechanism .…”