Melatonin-Induced Cytoskeleton Reorganization Leads to Inhibition of Melanoma Cancer Cell Proliferation

Abstract

Neuroindole melatonin, a hormone synthesized during the night mainly—but not exclusively—by the pineal gland of all vertebrates, functions as an adapting signal to the light-dark cycle. Its antioxidant, neuroprotective, anti-inflammatory, and antitumor properties are all well-known and widely reported. Melanoma is one of the most common carcinomas among developed countries and a type of tumor particularly difficult to fight back in medium/advanced stages. In contrast to other types of cancer, influence of melatonin on melanoma has been scarcely investigated. Thus, we have chosen the murine melanoma model B16-F10 cell line to study antiproliferative and antitumoral actions of melatonin. For this purpose, we combined both, cell culture and in vivo models. Melatonin reduced either, growth rate or migration of B16-F10 cells. Furthermore, melanin synthesis was altered by melatonin, promoting its synthesis. Melatonin also induced a G2/M cell cycle arrest and altered the cytoskeletal organization. To corroborate these results, we tested the effect of melatonin in the in vivo model of B16-F10 cell injection in the tail vein, which causes numerous lung metastases. Two different strategies of melatonin administration were used, namely, in drinking water, or daily intraperitoneal injection. However, contrary to what occurred in cell culture, no differences were observed between control and melatonin treated groups. Results obtained led us to conclude that melatonin exerts an antiproliferative and anti-migrating effect on this melanoma model by interfering with the cytoskeleton organization, but this pharmacological effect cannot be translated in vivo as the indole did not prevent metastasis in the murine model, suggesting that further insights into the effects of the indole in melanoma cells should be approached to understand this apparent paradox.

Melatonin Induces Melanogenesis in Human SK-MEL-1 Melanoma Cells Involving Glycogen Synthase Kinase-3 and Reactive Oxygen Species

“…In summary, herein we report that melatonin stimulates ROS generation and GSK-3β activity which in turn promote melanogenesis in SKMEL-1 cells. Activation of melanogenesis by melatonin in melanoma cells is likely more frequent than described so far; for example, Alvarez-Artime et al reported recently that the indoleamine stimulates pigmentation in murine BF16-F10 melanoma cells [36]. However, we have also explored the effect of melatonin on MEL-HO-a human melanoma cell line that is resistant to melanogenic stimuli-and found that the indoleamine reduced the cell proliferation without evidences of toxicity or melanogenesis induction.…”

“…Melatonin displays a variety of biological properties and one of the first effects described was the lightening of the skin of amphibians. Melatonin also attenuates melanogenesis in some mammals and it stimulates or reduces melanogenesis in cultured cells from rodent melanomas [36,37]. In human melanocytes, melatonin appears not to have a major influence on the pigmentation [38].…”

Melatonin Relations with Energy Metabolism as Possibly Involved in Fatal Mountain Road Traffic Accidents

“…The synchronizing role of melatonin in higher animals extends from the central nervous system up to peripheral oscillators in the cardiovascular system, skin, liver, adrenals, and various primate fetal tissues. Beside its crucial role as a circadian rhythm regulator, melatonin functions as a free radical scavenger and antioxidant agent [84], as well as, a neuroprotective [90], anti-inflammatory [91,92], and immunoregulating molecule [91], and even an oncostatic factor [84,93,94]. Melatonin, moreover, enhances carotid body chemoreceptor sensitivity [95] and lowers body temperature [77,96,97].…”

“…Tissue melatonin content increases in response to stressful conditions in plants [146], as well as in animals [131,132]. Beyond its role in supporting circadian rhythmicity, melatonin protects via antioxidant [84,[147][148][149], anti-inflammatory [91,92], and oncostatic effects [94]. Melatonin limits ROS formation [150] and reduces photosynthesis, a known source of ROS [85].…”

Melatonin inhibits growth of B16 melanoma in C57BL/6 mice

“…Several studies reported on the anti-tumor actions of melatonin against malignant melanoma both in vitro or in vivo (6,16,(23)(24)(25)(26)(27)(28). Thus, the present study was undertaken to assess the ability of orally-administered melatonin, an otherwise non-toxic chemoprotective agent against malignant B16-F10 melanoma cells subcutaneously injected into C57BL/6 mice.…”