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Melatonin antiproliferative effects require active mitochondrial function in embryonal carcinoma cells
Rute Loureiro1, Silvia Magalhães-Novais1,2, Katia A Mesquita1,2
1CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Abstract:
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.
Insights
Melatonin
Area of Science:
- Cancer Biology
- Cell Metabolism
- Pharmacology
Background:
- Melatonin exhibits oncostatic and cytotoxic effects in cancer cells.
- The precise mechanisms and metabolic context of melatonin's antitumoral actions require further elucidation.
Purpose of the Study:
- To investigate the impact of melatonin on P19 embryonal carcinoma stem cells (CSCs) and their differentiated cells.
- To explore the role of cellular metabolism (glycolysis vs. mitochondrial oxidative metabolism) in mediating melatonin's effects.
Main Methods:
- Culturing P19 CSCs and differentiated cells in high glucose or galactose (glucose-free) media.
- Assessing cell proliferation, cell cycle progression, oxygen consumption, gene expression (BCL-2), and cell death pathways.
- Evaluating the synergistic effects of melatonin combined with dichloroacetate (DCA).
Main Results:
- Highly glycolytic P19 CSCs showed reduced susceptibility to melatonin's antitumoral effects compared to cells with higher oxidative metabolism.
- Melatonin treatment led to S-phase arrest, reduced oxygen consumption, decreased BCL-2 expression, and caspase-3-independent cell death.
- Combined melatonin and DCA treatment exhibited synergistic effects in galactose medium and inhibited resistant P19 CSCs.
Conclusions:
- Melatonin's antiproliferative activity in P19 carcinoma cells is mitochondrially mediated.
- This mitochondrial action potentiates the effects of dichloroacetate, even in cells with a predominantly glycolytic phenotype.
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