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Title: Melatonin antiproliferative effects require active mitochondrial function in embryonal carcinoma cells
Authors: Loureiro, Rute
Magalhães-Novais, Sílvia 
Mesquita, Katia A. 
Baldeiras, Inês 
Sousa, Isabel S. 
Tavares, Ludgero C. 
Barbosa, Inês A. 
Oliveira, Paulo J. 
Vega-Naredo, Ignacio 
Keywords: cancer stem cells; dichloroacetate; melatonin; metabolism; mitochondria
Issue Date: 10-Jul-2015
Publisher: Impact Journals
Project: This work was performed with funding from Fundação Montepio Geral, FCT - Portuguese Foundation for Science and Technology (Pest-C/SAU/LA0001/2013–2014, PTDC/ QUI-BIQ/101052/2008, PTDC-SAU-TOX-117912–2010, and PTDC/DTP-FTO/1180/2012) co-funded by FEDER (QREN), through Programa Mais Centro under projects CENTRO-07-ST24-FEDER-002002, CENTRO-07-ST24- FEDER-002006 and CENTRO-07-ST24-FEDER-002008, and through Programa Operacional Factores de Competitividade - COMPETE and National funds. The FCT also supported Mesquita KA (SFRH/BD/66138/2009). Vega-Naredo I acknowledges the program “Clarín” de Ayudas Postdoctorales del Principado de Asturias (ACB14–20) co-funded by a Marie Curie COFUND action (7th Framework Programme of the European Commission). 
Serial title, monograph or event: Oncotarget
Volume: 6
Issue: 19
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.
ISSN: 1949-2553
DOI: 10.18632/oncotarget.4012
Rights: openAccess
Appears in Collections:FCTUC Ciências da Vida - Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais

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