Associação Portuguesa de Investigação em Cancro
Melatonin antiproliferative effects require active mitochondrial function in embryonal carcinoma cells
Melatonin antiproliferative effects require active mitochondrial function in embryonal carcinoma cells
A research team from the Center for Neuroscience and Cell Biology of the University of Coimbra published a new original article in the journal Oncotarget about the differentiation of cancer stem cells and their resistance to therapy.
In our previous study (Cell Death Differ. 2014; 21:1560-74), we compared mitochondrial physiology and metabolism between P19 cancer stem cells (CSCs) before/after differentiation and presented a unique fingerprint of the association between mitochondrial activity, cell differentiation and stemness. In comparison with their differentiated counterparts (dCCs), pluripotency of P19 CSCs was correlated with a strong glycolytic profile and decreased mitochondrial biogenesis and complexity. This decreased mitochondrial capacity increased their resistance against dichloroacetate (DCA). Thus, stimulation of mitochondrial function by growing P19 CSCs in glutamine/pyruvate-containing medium reduced their glycolytic phenotype, induced loss of pluripotent potential, compromised differentiation and became P19 CSCs sensitive to DCA. Because of the central role of this type of stem cells in teratocarcinoma development, our findings highlight the importance of mitochondrial metabolism in stemness, proliferation, differentiation and chemoresistance. In the new article published in Oncotarget we investigated the role of melatonin in cancer stem cells. Our results ascribes an anti-tumor effect for melatonin only in differentiated cancer cells with an active oxidative metabolism, triggering a type of mitochondrial-mediated cell death which is likely to be characterized by an arrest at S-phase, reduction of the mitochondrial electron transport chain (ETC), generation of reactive oxygen species, BCL-2 down-regulation and AIF release. Thus, the treatment with melatonin and the stimulation of mitochondrial metabolism constitute promissory strategies against resistant cancer stem cells.
Authors and Affiliations:
Loureiro R1, Magalhães-Novais S1,2, Mesquita KA1,2, Baldeiras I1,3, Sousa IS1,2, Tavares LC1,2, Barbosa IA1, Oliveira PJ1, Vega-Naredo I1,4.
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.
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.
Journal: Oncotarget
