Melatonin receptors in human uveal melanocytes and melanoma cells

Abstract

Previous work has demonstrated that melatonin inhibits growth of cultured human uveal melanoma cells. The goal of this study was to determine the expression of mRNA encoding the melatonin receptor subtypes and the effect of specific melatonin receptor agonists on cell growth of uveal melanoma cells and melanocytes. RNA expression of the human melatonin Mel1a and Mel1b receptor subtypes was determined by reverse transcription‐polymerase chain reaction (RT‐PCR) amplification of RNA isolated from two melanoma cell lines and from one cell line of normal melanocytes. PCR‐amplified cDNA encoding the Mel1b melatonin receptor subtype, but not the Mel1a subtype, was detected in reverse‐transcribed RNA obtained from both normal uveal melanocytes and melanoma cell lines. Uveal melanoma cells and melanocytes were cultured for 24 hr, then melatonin or one of its membrane receptor agonists, 6‐chloromelatonin (Mel1a–1b) or S‐20098 (Mel1b) or its putative nuclear agonist, CGP‐52608 (Mel2), was added to the medium. After 5 days, the cells were detached, counted, and compared to untreated controls. Melatonin and its membrane receptor agonists (Mel1a–1b and Mel1b ), but not its putative nuclear receptor agonist (Mel2), inhibited the growth of uveal melanoma cells, but not normal melanocytes, at very low concentrations. In uveal melanoma cells, the expression of RNA encoding the Mel1b receptor suggests that the growth inhibiting effect of melatonin on uveal melanoma cells is related to activation of the melatonin Mel1b membrane receptor. Furthermore, the expression of RNA encoding melatonin receptors in normal uveal melanocytes suggests that melatonin may play a role in the function of these cells.

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

“…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). In estrogen-receptor positive breast cancer cells, the expression of ROR· was found to clearly contribute to melatonin-induced growth inhibition (70).…”

“…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).…”

Occupational exposure to endocrine-disrupting chemicals and the risk of uveal melanoma

“…Such occupations include, among others, farm workers (exposed to pesticides) (7,8), metal workers (exposed to endocrinally active heavy metals and metalworking fluids) (7)(8)(9), welders (possibly exposed to organic solvents and heavy metals) (10), medical and dental workers (potentially exposed to heavy metals and bisphenol A) (7,10), workers in the leather industry (exposure to heavy metals and solvents) (9), and workers in the chemical industry (10). Although epidemiological evidence for exposure to EDC has so far been inconsistent (11)(12)(13)(14), laboratory studies suggest that melanoma cells may be influenced by hormonal factors (15).…”

Therapeutic Actions of Melatonin in Cancer: Possible Mechanisms

“…120 In another study, the growth inhibitory effect of melatonin was demonstrated at a concentration of 2 nM, the physiological concentration found in aqueous humor; the growth inhibiting effect of melatonin on uveal melanoma cells was shown to be related to activation of MT 1 melatonin receptors. 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).…”