Research Papers:

Melatonin antiproliferative effects require active mitochondrial function in embryonal carcinoma cells

Rute Loureiro _, Silvia Magalhães-Novais, Katia A. Mesquita, Ines Baldeiras, Isabel S. Sousa, Ludgero C. Tavares, Ines A. Barbosa, Paulo J. Oliveira and Ignacio Vega-Naredo

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Oncotarget. 2015; 6:17081-17096. https://doi.org/10.18632/oncotarget.4012

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Rute Loureiro1, Silvia Magalhães-Novais1,2, Katia A. Mesquita1,2, Ines Baldeiras1,3, Isabel S. Sousa1,2, Ludgero C. Tavares1,2, Ines A. Barbosa1, Paulo J. Oliveira1, Ignacio Vega-Naredo1,4

1CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

2Department of Life Sciences, University of Coimbra, Coimbra, Portugal

3School of Medicine, University of Coimbra, Coimbra, Portugal

4Department of Morphology and Cell Biology, University of Oviedo, Oviedo, Spain

Correspondence to:

Ignacio Vega-Naredo, e-mail: [email protected]

Keywords: melatonin, mitochondria, metabolism, dichloroacetate, cancer stem cells

Received: January 19, 2015     Accepted: May 08, 2015     Published: May 20, 2015


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.

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