Melatonin antiproliferative effects require active mitochondrial function in embryonal carcinoma cells

Although melatonin oncostatic and cytotoxic effects have been described in different types of cancer cells, the specific mechanisms leading to its antitumoral effects and their metabolic context specificity are still not completely understood. Here, we evaluated the effects of melatonin in P19 embry...

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Published in:Oncotarget 2015-07, Vol.6 (19), p.17081-17096
Main Authors: Loureiro, Rute, Magalhães-Novais, Silvia, Mesquita, Katia A, Baldeiras, Ines, Sousa, Isabel S, Tavares, Ludgero C, Barbosa, Ines A, Oliveira, Paulo J, Vega-Naredo, Ignacio
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Blotting, Western
Cell Line, Tumor
Cell Proliferation - drug effects
Embryonal Carcinoma Stem Cells - drug effects
Embryonal Carcinoma Stem Cells - metabolism
Humans
Melatonin - pharmacology
Membrane Potential, Mitochondrial - drug effects
Mitochondria - drug effects
Neoplastic Stem Cells - drug effects
Neoplastic Stem Cells - metabolism
Research Paper
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Summary:Although melatonin oncostatic and cytotoxic effects have been described in different types of cancer cells, the specific mechanisms leading to its antitumoral effects and their metabolic context specificity are still not completely understood. Here, we evaluated the effects of melatonin in P19 embryonal carcinoma stem cells (CSCs) and in their differentiated counterparts, cultured in either high glucose medium or in a galactose (glucose-free) medium which leads to glycolytic suppression and increased mitochondrial metabolism. We found that highly glycolytic P19 CSCs were less susceptible to melatonin antitumoral effects while cell populations relying on oxidative metabolism for ATP production were more affected. The observed antiproliferative action of melatonin was associated with an arrest at S-phase, decreased oxygen consumption, down-regulation of BCL-2 expression and an increase in oxidative stress culminating with caspase-3-independent cell death. Interestingly, the combined treatment of melatonin and dichloroacetate had a synergistic effect in cells grown in the galactose medium and resulted in an inhibitory effect in the highly resistant P19 CSCs. Melatonin appears to exert its antiproliferative activity in P19 carcinoma cells through a mitochondrially-mediated action which in turn allows the amplification of the effects of dichloroacetate, even in cells with a more glycolytic phenotype.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.4012